4-Imidazolyl substituted pyrimidine derivatives with cdk inhibitory activity

ABSTRACT

Compounds of the formula (I): wherein R 1 , R 2 , R 3 , R 4 , R 5  and p are as defined within and a pharmaceutically acceptable salts and in vivo hydrolysable esters are described. Also described are processes for their preparation and their use as medicaments, particularly medicaments for producing a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal, such as man.

The invention relates to pyrimidine derivatives, or pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, which possess cell-cycle inhibitory activity and are accordingly useful for their anti-cell-proliferation (such as anti-cancer) activity and are therefore useful in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said pyrimidine derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cell-proliferation effect in a warm-blooded animal such as man.

A family of intracellular proteins called cyclins play a central role in the cell cycle. The synthesis and degradation of cyclins is tightly controlled such that their level of expression fluctuates during the cell cycle. Cyclins bind to cyclin-dependent serine/threonine kinases (CDKs) and this association is essential for CDK (such as CDK1, CDK2, CDK4 and/or CDK6) activity within the cell. Although the precise details of how each of these factors combine to regulate CDK activity is poorly understood, the balance between the two dictates whether or not the cell will progress through the cell cycle.

The recent convergence of oncogene and tumour suppressor gene research has identified regulation of entry into the cell cycle as a key control point of mitogenesis in tumours. Moreover, CDKs appear to be downstream of a number of oncogene signalling pathways. Disregulation of CDK activity by upregulation of cyclins and/or deletion of endogenous inhibitors appears to be an important axis between mitogenic signalling pathways and proliferation of tumour cells.

Accordingly it has been recognised that an inhibitor of cell cycle kinases, particularly inhibitors of CDK2, CDK4 and/or CDK6 (which operate at the S-phase, G1-S and G1-S phase respectively) should be of value as a selective inhibitor of cell proliferation, such as growth of mammalian cancer cells.

The present invention is based on the discovery that certain pyrimidine compounds surprisingly inhibit the effects of cell cycle kinases showing selectivity for CDK2, CDK4 and CDK6, and thus possess anti-cell-proliferation properties. Such properties are expected to be of value in the treatment of disease states associated with aberrant cell cycles and cell proliferation such as cancers (solid tumours and leukemias), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.

Accordingly, the present invention provides a compound of formula (I):

wherein:

R¹ is halo, cyano, C₁₋₃alkyl or C₁₋₃alkoxy;

p is 0-2; wherein the values of R¹ may be the same or different;

R² is hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl, a heterocyclyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more hydroxy, methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by one or more methyl, ethyl, acetyl, 2,2,2-trifluoroethyl or methoxyethyl;

R³ is hydrogen, halo or cyano;

R⁴ is C₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆allyl;

R⁵ is substituted methyl, optionally substituted C₂₋₄alkyl, C₃₋₆cycloalkyl or optionally substituted C₂₋₆alkenyl; wherein said substituents are selected from one or more hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, phenyl, methylamino, ethylamino, dimethylamino, diethylamino, methylthio, ethylthio, propylthio, isopropylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl, isopropylsulphinyl, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl or cyclopropylmethoxy;

or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; provided that the compound is not 4-(1-methyl-2-ethylimidazol-S-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine; or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl) sulphamoyl]anilino}pyrimidine.

According to a further feature of the present invention there is provided a compound of formula (I) (as depicted above) wherein:

R¹ is halo, cyano, C₁₋₃alkyl or C₁₋₃alkoxy;

p is 0-2; wherein the values of R¹ may be the same or different;

R² is C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl, a heterocyclyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by one or more methyl, ethyl, acetyl, 2,2,2-trifluoroethyl or methoxyethyl;

R³ is hydrogen, halo or cyano;

R⁴ is C₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl;

R⁵ is substituted methyl, optionally substituted C₂₋₆alkyl or optionally substituted C₂₋₆alkenyl; wherein said substituents are selected from one or more methoxy, ethoxy, propoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; provided that the compound is not 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-trifluoromethylimidazol-5-yl)-2-{4[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl) anilino]pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl) anilino]pyrimidine; or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl) sulphamoyl]anilino}pyrimidine.

According to a further feature of the present invention there is provided a compound of formula (I) (as depicted above) wherein:

R¹ is halo, cyano, C₁₋₃alkyl or C₁₋₃alkoxy;

p is 0-2; wherein the values of R¹ may be the same or different;

R² is C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄ayl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃allyl, a heterocyclyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by one or more methyl, ethyl, acetyl, 2,2,2-trifluoroethyl or methoxyethyl;

R³ is hydrogen, halo or cyano;

R₄ is C₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl;

R⁵ is substituted methyl, optionally substituted C₂₋₆alkyl, C₃₋₆cycloalkyl or optionally substituted C₂₋₆alkenyl; wherein said substituents are selected from one or more hydroxy, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy;

or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; provided that the compound is not 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-trifluoromethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl) anilino]pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl) anilino]pyrimidine; or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl) sulphamoyl]anilino}pyrimidine.

In this specification the term “alkyl” includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only. For example, “C₁₋₆alkyl”, “C₂₋₆alkyl”, “C₁₋₄alkyl” and “C₁₋₃alkyl” include propyl, isopropyl and t-butyl. However, references to individual alkyl groups such as ‘propyl’ are specific for the straight chained version only and references to individual branched chain alkyl groups such as ‘isopropyl’ are specific for the branched chain version only. A similar convention applies to other radicals, for example “C₃₋₆cycloalkylC₁₋₃alkyl” includes cyclopropylmethyl, 1-cyclobutylethyl and 3-cyclopropylpropyl. The term “halo” refers to fluoro, chloro, bromo and iodo.

Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

A “heterocyclyl” is a saturated, partially saturated or unsaturated, monocyclic ring containing 4-6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, and a ring sulphur atom may be optionally oxidised to form the S-oxide(s). Examples and suitable values of the term “heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, thienyl, thiadiazolyl, piperazinyl, thiazolidinyl, thiomorpholino, pyrrolinyl, tetrahydropyranyl, tetrahydrofuryl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl and isoxazolyl. Suitably a “heterocyclyl” is tetrahydrofuryl.

Examples of “C₁₋₃alkoxy” include, methoxy, ethoxy and propoxy. Examples of “C₂₋₆alkenyl” and “C₂₋₄alkenyl” are vinyl, allyl and 1-propenyl. Examples of “C₂₋₄alkynyl” are ethynyl, 1-propynyl and 2-propynyl. Examples of “C₃₋₆cycloalkyl” are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of “heterocyclylC₁₋₃alkyl” include pyridylmethyl, 3-morpholinopropyl and 2-pyrimid-2-ylethyl. Examples of “C₁₋₆alkoxyC₁₋₆alkyl” and “C₁₋₄alkoxyC₁₋₄alkyl” are methoxymethyl, 2-methoxyethyl and 2-ethoxypropyl.

A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

An in vivo hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include C₁₋₆alkoxymethyl esters for example methoxymethyl, C₁₋₆alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.

Some compounds of the formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z-isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess CDK inhibitory activity.

The invention relates to any and all tautomeric forms of the compounds of the formula (I) that possess CDK inhibitory activity. In particular the skilled reader will appreciate that when R⁴ is hydrogen, the imidazole ring as drawn in formula (I) may tautomerise.

It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess CDK inhibitory activity.

Suitable values of R¹, R², R³, R⁴, R⁵ and p are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore.

R¹ is fluoro, chloro, cyano, methyl, ethyl, methoxy or ethoxy.

p is 0.

p is 1.

p is 2; wherein the values of R¹ may be the same or different.

R² is C₁₋₄allyl, C₂₋₄alkenyl, C₃cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more methyl, methoxy, ethoxy, trifluoromethyl.

R² is C₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more methoxy, ethoxy, trifluoromethyl.

R₂ is hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more hydroxy, methoxy, ethoxy or trifluoromethyl.

R² is methyl, ethyl, propyl, t-butyl, allyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or tetrahydrofur-2-ylmethyl; wherein R² may be optionally substituted on carbon by one or more methyl, methoxy, ethoxy, trifluoromethyl.

R² is methyl, ethyl, propyl, t-butyl, allyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or tetrahydrofur-2-ylmethyl; wherein R² may be optionally substituted on carbon by one or more methoxy, ethoxy, trifluoromethyl.

R² is hydrogen, methyl, ethyl, propyl, t-butyl, allyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or tetrahydrofur-2-ylmethyl; wherein R² may be optionally substituted on carbon by one or more hydroxy, methoxy, ethoxy, trifluoromethyl.

R² is 2-ethoxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 3-methoxypropyl, t-butyl, allyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or tetrahydrofur-2-ylmethyl.

R² is hydrogen, 2-ethoxyethyl, 2-methoxyethyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 3-methoxypropyl, t-butyl, allyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or tetrahydrofur-2-ylmethyl.

R³ is hydrogen.

R⁴ is C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl.

R⁴ is C₁₋₆alkyl.

R⁴ is C₁₋₄alkyl.

R⁴ is methyl, ethyl, isopropyl or 1-methoxyprop-2-yl.

R⁴ is methyl, ethyl, propyl, isopropyl or 1-methoxyprop-2-yl.

R⁵ is substituted methyl or optionally substituted C₂₋₆alkyl; wherein said substituents are selected from one or more methoxy.

R⁵ is substituted methyl, C₃₋₆cycloalkyl, optionally substituted C₂₋₆alkenyl or optionally substituted C₂₋₆alkyl; wherein said substituents are selected from one or more methoxy or hydroxy.

R⁵ is substituted methyl, optionally substituted C₂₋₆alkyl, C₃₋₆cycloalkyl or optionally substituted C₂₋₆alkenyl; wherein said substituents are selected from one or more hydroxy, methoxy, ethoxy, isopropoxy, phenyl, ethylamino, dimethylamino, methylthio, ethylthio, isopropylthio, ethylsulphinyl or ethylsulphonyl.

R⁵ is methoxymethyl, isopropyl, ethyl, butyl or 3,3-dimethylbutyl.

R⁵ is methoxymethyl, 2-methoxyethyl, 2-hydroxy-2-methylpropyl, propyl, isopropyl, ethyl, butyl, isobutyl, cyclopropyl, 2-methyl-1-propenyl, 3-butenyl, 1-propenyl or 3,3-dimethylbutyl.

R⁵ is methoxymethyl, 2-methoxyethyl, 2-hydroxy-2-methylpropyl, propyl, isopropyl, ethyl, butyl, isobutyl, cyclopropyl, 2-methyl-1-propenyl, 3-butenyl, 1-propenyl, 3,3-dimethylbutyl, phenethyl, dimethylaminomethyl, ethylaminomethyl, ethoxymethyl, methylthiomethyl, isopropylthiomethyl, ethylthiomethyl, ethylsulphinlmethyl, ethylsulphonylmethyl or isopropoxymethyl.

Therefore in another aspect of the invention, there is provided a compound of formula (I) (as depicted above) wherein:

p is 0;

R² is C₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more methoxy, ethoxy, trifluoromethyl;

R³ is hydrogen;

R⁴ is C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl;

R⁵ is substituted methyl or optionally substituted C₂₋₆alkyl; wherein said substituents are selected from one or more methoxy;

or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; provided that the compound is not 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-trifluoromethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl) anilino]pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl) anilino]pyrimidine; or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl) sulphamoyl]anilino}pyrimidine.

Therefore in another aspect of the invention, there is provided a compound of formula (I) (as depicted above) wherein:

p is 0;

R² is C₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more methoxy, ethoxy, trifluoromethyl;

R³ is hydrogen;

R⁴ is C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl;

R⁵ is substituted methyl, C₃₋₆cycloalkyl, optionally substituted C₂₋₆alkenyl or optionally substituted C₂₋₆alkyl; wherein said substituents are selected from one or more methoxy or hydroxy;

or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; provided that the compound is not 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-trifluoromethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl) anilino]pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl) anilino]pyrimidine; or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl) sulphamoyl]anilino}pyrimidine.

Therefore in another aspect of the invention, there is provided a compound of formula (I) (as depicted above) wherein:

p is 0;

R² is hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more hydroxy, methoxy, ethoxy or trifluoromethyl;

R³ is hydrogen;

R⁴ is C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl; or

R⁵ is substituted methyl, optionally substituted C₂ alkyl, C₃₋₆cycloalkyl or optionally substituted C₂₋₆alkenyl; wherein said substituents are selected from one or more hydroxy, methoxy, ethoxy, isopropoxy, phenyl, ethylamino, dimethylamino, methylthio, ethylthio, isopropylthio, ethylsulphinyl or ethylsulphonyl;

or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; provided that the compound is not 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine; or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl) sulphamoyl]anilino}pyrimidine.

Therefore in an additional aspect of the invention, there is provided a compound of formula (I) (as depicted above) wherein:

p is 0;

R² is 2-ethoxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 3-methoxypropyl, t-butyl, allyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or tetrahydrofur-2-ylmethyl;

R³ is hydrogen;

R⁴ is methyl, ethyl, isopropyl or 1-methoxyprop-2-yl;

R⁵ is methoxymethyl, isopropyl, ethyl, butyl or 3,3-dimethylbutyl;

or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; provided that the compound is not 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-trifluoromethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl) anilino]pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl) anilino]pyrimidine; or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl) sulphamoyl]anilino}pyrimidine.

Therefore in an additional aspect of the invention, there is provided a compound of formula (I) (as depicted above) wherein:

p is 0;

R² is 2-ethoxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 3-methoxypropyl, t-butyl, allyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or tetrahydrofur-2-ylmethyl;

R³ is hydrogen;

R⁴ is methyl, ethyl, propyl, isopropyl or 1-methoxyprop-2-yl;

R⁵ is methoxymethyl, 2-methoxyethyl, 2-hydroxy-2-methylpropyl, propyl, isopropyl, ethyl, butyl, isobutyl, cyclopropyl, 2-methyl-1-propenyl, 3-butenyl, 1-propenyl or 3,3-dimethylbutyl;

or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; provided that the compound is not 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-trifluoromethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl) anilino]pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl) anilino]pyrimidine; or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl) sulphamoyl]anilino}pyrimidine.

Therefore in an additional aspect of the invention, there is provided a compound of formula (I) (as depicted above) wherein:

p is 0;

R² is hydrogen, 2-ethoxyethyl, 2-methoxyethyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 3-methoxypropyl, t-butyl, allyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or tetrahydrofur-2-ylmethyl;

R³ is hydrogen;

R⁴ is methyl, ethyl, propyl, isopropyl or 1-methoxyprop-2-yl; or

R⁵ is methoxymethyl, 2-methoxyethyl, 2-hydroxy-2-methylpropyl, propyl, isopropyl, ethyl, butyl, isobutyl, cyclopropyl, 2-methyl-1-propenyl, 3-butenyl, 1-propenyl, 3,3-dimethylbutyl, phenethyl, dimethylaminomethyl, ethylaminomethyl, ethoxymethyl, methylthiomethyl, isopropylthiomethyl, ethylthiomethyl, ethylsulphinlmethyl, ethylsulphonylmethyl or isopropoxymethyl;

or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; provided that the compound is not 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine; or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine.

In another aspect of the invention, particular compounds of the invention are any one of the Examples or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.

In another aspect of the invention, particular compounds of the invention are one of Examples 4, 12, 30, 31, 44, 51, 54, 58, 60 or 61 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.

A particular aspect of the invention is that which relates to the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof which process (wherein R¹, R², R³, R⁴, R⁵ and p are, unless otherwise specified, as defined in formula (I)) comprises of: Process a) reaction of a pyrimidine of formula (II):

wherein L is a displaceable group; with an aniline of formula (III):

Process b) reacting a compound of formula (IV):

with a compound of formula (V):

wherein T is O or S; Rx may be the same or different and is C₁₋₆alkyl; Process c) reacting a pyrimidine of formula (VI):

wherein X is a displaceable group; with an amine of formula (VII): R²—NH₂  (VII) or Process d) reacting a pyrimidine of formula (VIII)

with a compound of formula (IX):

where Y is a displaceable group; and thereafter if necessary:

-   i) converting a compound of the formula (I) into another compound of     the formula (I); -   ii) removing any protecting groups; -   iii) forming a pharmaceutically acceptable salt or in vivo     hydrolysable ester.

L is a displaceable group, suitable values for L are for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group.

X is a displaceable group, suitable values for X are for example, a fluoro or chloro group. Preferably X is fluoro.

Y is a displaceable group, suitable values for Y are for example, a halogeno or sulphonyloxy group, for example a bromo, iodo or trifluoromethanesulphonyloxy group. Preferably Y is iodo.

Specific reaction conditions for the above reactions are as follows.

Process a) Pyrimidines of formula (I) and anilines of formula (III) may be reacted together:

-   i) in the presence of a suitable solvent for example a ketone such     as acetone or an alcohol such as ethanol or butanol or an aromatic     hydrocarbon such as toluene or N-methylpyrrolidine, optionally in     the presence of a suitable acid for example an inorganic acid such     as hydrochloric acid or sulphuric acid, or an organic acid such as     acetic acid or formic acid (or a suitable Lewis acid) and at a     temperature in the range of 0° C. to reflux, preferably reflux; or -   ii) under standard Buchwald conditions (for example see J. Am. Chem.     Soc., 118, 7215; J. Am. Chem. Soc., 119, 8451; J. Org. Chem., 62,     1568 and 6066) for example in the presence of palladium acetate, in     a suitable solvent for example an aromatic solvent such as toluene,     benzene or xylene, with a suitable base for example an inorganic     base such as caesium carbonate or an organic base such as     potassium-t-butoxide, in the presence of a suitable ligand such as     2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and at a temperature in     the range of 25 to 80° C.

Pyrimidines of the formula (II) where L is chloro may be prepared according to Scheme 1:

Anilines of formula (III) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Process b) Compounds of formula (IV) and compounds of formula (V) are reacted together in a suitable solvent such as N-methylpyrrolidinone or butanol at a temperature in the range of 100-200° C., preferably in the range of 150-170° C. The reaction is preferably conducted in the presence of a suitable base such as, for example, sodium hydride, sodium methoxide or potassium carbonate.

Compounds of formula (V) may be prepared according to Scheme 2:

Compounds of formula (IV) and (Va) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. Process c) Compounds of formula (VI) and amines of formula (VII) may be reacted together in the presence of an inert solvent such as N-methylpyrrolidinone or pyridine, in the presence of a base for example an inorganic base such as caesium carbonate or in the presence of an organic base such as excess (VII) and at a temperature in the range of 25 to 80° C.

Compounds of formula (VI) (wherein X is chloro) may be prepared according to Scheme 3:

Compounds of formula (VIa) may be prepared according to Process a, Process b or Process d but wherein compounds (III), (IV) and (IX) are not substituted by R²NHSO₂—. Process d) Compounds of formula (VIII) and amines of formula (IX) may be reacted together under standard Buchwald conditions as described in Process a.

The synthesis of compounds of formula (VIII) is described in Scheme 1.

Compounds of formula (IX) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Amines of formula (VI) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.

As stated hereinbefore the compounds defined in the present invention possesses anti-cell-proliferation activity such as anti-cancer activity which is believed to arise from the CDK inhibitory activity of the compound. These properties may be assessed, for example, using the procedures set out in WO 02/04429.

Although the pharmacological properties of the compounds of the formula (I) vary with structural change, in general activity possessed by compounds of the formula a) may be demonstrated at IC₅₀ concentrations or doses in the range 250 μM to 1 nM in the in vitro assay described in WO 02/04429.

Typical IC₅₀ values for compounds of the invention when tested in the SRB assay described in WO 02/04429 are in the range 1 mM to 1 nM.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a pyrimidine derivative of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventional manner using conventional excipients.

The compound of formula (I) will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient. Preferably a daily dose in the range of 1-50 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.

According to a further aspect of the present invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.

We have found that the compounds defined in the present invention, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, are effective cell cycle inhibitors (anti-cell proliferation agents), which property is believed to arise from their CDK inhibitory properties. Accordingly the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by CDK enzymes, i.e. the compounds may be used to produce a CDK inhibitory effect in a warm-blooded animal in need of such treatment. Thus the compounds of the present invention provide a method for treating the proliferation of malignant cells characterised by inhibition of CDK enzymes, i.e. the compounds may be used to produce an anti-proliferative effect mediated alone or in part by the inhibition of CDKs. Such a compound of the invention is expected to possess a wide range of anti-cancer properties as CDKs have been implicated in many common human cancers such as leukaemia and breast, lung, colon, rectal, stomach, prostate, bladder, pancreas and ovarian cancer. Thus it is expected that a compound of the invention will possess anti-cancer activity against these cancers. It is in addition expected that a compound of the present invention will possess activity against a range of leukaemias, lymphoid malignancies and solid tumours such as carcinomas and sarcomas in tissues such as the liver, kidney, prostate and pancreas. In particular such compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, breast, prostate, lungs and skin. More particularly such compounds of the invention, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with CDKs, especially those tumours which are significantly dependent on CDKs for their growth and spread, including for example, certain tumours of the colon, breast, prostate, lung, vulva and skin. Particularly “cancer” is selected from leukaemia, breast cancer, lung cancer, colorectal cancer, stomach cancer, prostate cancer, bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, kidney cancer, skin cancer and cancer of the vulva.

It is further expected that a compound of the present invention will possess activity against other cell-proliferation diseases in a wide range of other disease states including leukaemias, fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.

Thus according to this aspect of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore for use as a medicament; and the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal such as man. Particularly, an inhibitory effect is produced by preventing entry into or progression through the S phase by inhibition of CDK2, CDK4 and/or CDK6, especially CDK2.

According to a further feature of the invention, there is provided a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein before in the manufacture of a medicament for use in the treatment of cancers (solid tumours and leukaemias), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation, particularly in the treatment of cancers.

According to a further feature of this aspect of the invention there is provided a method for producing a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound as defined immediately above. Particularly, an inhibitory effect is produced by preventing entry into or progression through the S phase by inhibition of CDK2, CDK4 and/or CDK6, especially CDK2.

According to a further feature of this aspect of the invention there is provided a method for producing a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof as defined herein before. Particularly, an inhibitory effect is produced by preventing entry into or progression through the S phase by inhibition of CDK2, CDK4 and/or CDK6, especially CDK2.

According to an additional feature of this aspect of the invention there is provided a method of treating cancers (solid tumours and leukaemias), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof as defined herein before.

Particularly there is provided a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof as defined herein before.

In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal such as man.

In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of cancers (solid tumours and leukaemias), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.

In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of cancer in a warm-blooded animal such as man.

Preventing cells from entering DNA synthesis by inhibition of essential S-phase initiating activities such as CDK2 initiation may also be useful in protecting normal cells of the body from toxicity of cycle-specific pharmaceutical agents. Inhibition of CDK2 or 4 will prevent progression into the cell cycle in normal cells which could limit the toxicity of cycle-specific pharmaceutical agents which act in S-phase, G2 or mitosis. Such protection may result in the prevention of hair loss normally associated with these agents.

Therefore in a further aspect of the invention there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use as a cell protective agent.

Therefore in a further aspect of the invention there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in preventing hair loss arising from the treatment of malignant conditions with pharmaceutical agents.

Examples of pharmaceutical agents for treating malignant conditions that are known to cause hair loss include alkylating agents such as ifosfamide and cyclophosphamide; antimetabolites such as methotrexate, 5-fluorouracil, gemcitabine and cytarabine; vinca alkaloids and analogues such as vincristine, vinbalstine, vindesine, vinorelbine; taxanes such as paclitaxel and docetaxel; topoisomerase I inhibitors such as irintotecan and topotecan; cytotoxic antibiotics such as doxorubicin, daunorubicin, mitoxantrone, actinomycin-D and mitomycin; and others such as etoposide and tretinoin.

In another aspect of the invention, the compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, may be administered in association with a one or more of the above pharmaceutical agents. In this instance the compound of formula (I) may be administered by systemic or non systemic means. Particularly the compound of formula (I) my may administered by non-systemic means, for example topical administration.

Therefore in an additional feature of the invention, there is provided a method of preventing hair loss during treatment for one or more malignant conditions with pharmaceutical agents, in a warm-blooded animal, such as man, which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.

In an additional feature of the invention, there is provided a method of preventing hair loss during treatment for one or more malignant conditions with pharmaceutical agents, in a warm-blooded animal, such as man, which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof in simultaneous, sequential or separate administration with an effective amount of said pharmaceutical agent.

According to a further aspect of the invention there is provided a pharmaceutical composition for use in preventing hair loss arising from the treatment of malignant conditions with pharmaceutical agents which comprises a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and said pharmaceutical agent, in association with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provided a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and a pharmaceutical agent for treating malignant conditions that is known to cause hair loss.

According to a further aspect of the present invention there is provided a kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt     or in vivo hydrolysable ester thereof, in a first unit dosage form; -   b) a pharmaceutical agent for treating malignant conditions that is     known to cause hair loss; in a second unit dosage form; and -   c) container means for containing said first and second dosage     forms.

According to another feature of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, in the manufacture of a medicament for the prevention of hair loss during treatment of malignant conditions with pharmaceutical agents.

According to a further aspect of the present invention there is provided a combination treatment for the prevention of hair loss comprising the administration of an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of a pharmaceutical agent for treatment of malignant conditions to a warm-blooded animal, such as man.

As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular cell-proliferation disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. A unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged.

The CDK inhibitory activity defined hereinbefore may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of such conjoint treatment in addition to the cell cycle inhibitory treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy. Such chemotherapy may cover three main categories of therapeutic agent:

-   (i) other cell cycle inhibitory agents that work by the same or     different mechanisms from those defined hereinbefore; -   (ii) cytostatic agents such as antioestrogens (for example     tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene),     progestogens (for example megestrol acetate), aromatase inhibitors     (for example anastrozole, letrazole, vorazole, exemestane),     antiprogestogens, antiandrogens (for example flutamide, nilutamide,     bicalutamide, cyproterone acetate), LHRH agonists and antagonists     (for example goserelin acetate, luprolide), inhibitors of     testosterone 5α-dihydroreductase (for example finasteride),     anti-invasion agents (for example metalloproteinase inhibitors like     marimastat and inhibitors of urokinase plasminogen activator     receptor function) and inhibitors of growth factor function, (such     growth factors include for example platelet derived growth factor     and hepatocyte growth factor such inhibitors include growth factor     antibodies, growth factor receptor antibodies, tyrosine kinase     inhibitors and serine/threonine kinase inhibitors); and -   (iii) antiproliferative/antineoplastic drugs and combinations     thereof, as used in medical oncology, such as antimetabolites (for     example antifolates like methotrexate, fluoropyrimidines like     5-fluorouracil, purine and adenosine analogues, cytosine     arabinoside); antitumour antibiotics (for example anthracyclines     like doxorubicin, daunomycin, epirubicin and idarubicin,     mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for     example cisplatin, carboplatin); alkylating agents (for example     nitrogen mustard, melphalan, chlorambucil, busulphan,     cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic     agents (for example vinca alkaloids like vincristine and taxoids     like taxol, taxotere); topoisomerase inhibitors (for example     epipodophyllotoxins like etoposide and teniposide, amsacrine,     topotecan). According to this aspect of the invention there is     provided a pharmaceutical product comprising a compound of the     formula (I) as defined hereinbefore and an additional anti-tumour     substance as defined hereinbefore for the conjoint treatment of     cancer.

In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In the above other pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments of the compounds of the invention described herein also apply.

EXAMPLES

The invention will now be illustrated by the following non limiting examples in which, unless stated otherwise:

-   (i) temperatures are given in degrees Celsius (° C.); operations     were carried out at room or ambient temperature, that is, at a     temperature in the range of 18-25° C.; -   (ii) organic solutions were dried over anhydrous magnesium sulphate;     evaporation of solvent was carried out using a rotary evaporator     under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath     temperature of up to 60° C.; -   (iii) chromatography means flash chromatography on silica gel; thin     layer chromatography (TLC) was carried out on silica gel plates; -   (iv) in general, the course of reactions was followed by TLC and     reaction times are given for illustration only; -   (v) final products had satisfactory proton nuclear magnetic     resonance (NMR) spectra and/or mass spectral data; -   (vi) yields are given for illustration only and are not necessarily     those which can be obtained by diligent process development;     preparations were repeated if more material was required; -   (vii) when given, NMR data is in the form of delta values for major     diagnostic protons, given in parts per million (ppm) relative to     tetramethylsilane (TMS) as an internal standard, determined at 300     MHz using perdeuterio dimethyl sulphoxide (DMSO-d₆) as solvent     unless otherwise indicated; and peak multiplicities are shown as     follows: s, singlet; d, doublet; dd, double doublet; t, triplet; tt,     triple triplet; q, quartet; tq, triple quartet; m, multiplet; br,     broad; -   (viii) chemical symbols have their usual meanings; SI units and     symbols are used; -   (ix) solvent ratios are given in volume:volume (v/v) terms; and -   (x) mass spectra were run with an electron energy of 70 electron     volts in the chemical ionization (CI) mode using a direct exposure     probe; where indicated ionization was effected by electron impact     (EI), fast atom bombardment (FAB) or electrospray (ESP); values for     m/z are given; generally, only ions which indicate the parent mass     are reported; and unless otherwise stated, the mass ion quoted is     (MH)⁺; -   (xi) unless stated otherwise compounds containing an asymmetrically     substituted carbon and/or sulphur atom have not been resolved; -   (xii) where a synthesis is described as being analogous to that     described in a previous example the amounts used are the millimolar     ratio equivalents to those used in the previous example; -   (xvi) the following abbreviations have been used:     -   DMF dimethylformamide;     -   EtOAc ethyl acetate;     -   ether diethyl ether;     -   MeOH methanol; and     -   DCM dichloromethane; -   xvii) where an Isolute SCX-2 column is referred to, this means an     “ion exchange” extraction cartridge for adsorption of basic     compounds, i.e. a polypropylene tube containing a benzenesulphonic     acid based strong cation exchange sorbent, used according to the     manufacturers instructions obtained from International Sorbent     Technologies Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan,     UK, CF82 7RJ; -   xviii) where an Isolute amine column is referred to, this means an     “ion exchange” extraction cartridge for adsorption of acidic     compounds, i.e. a polypropylene tube containing a amino silane     covalently bonded to a silica particle used according to the     manufacturers instructions obtained from International Sorbent     Technologies Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan,     UK, CF82 7RJ; and -   xix) where a Chemelut column is referred to, this means an     extraction cartridge for removal of water, i.e. a polypropylene tube     containing diatomaceous earth used according to the manufacturers     instructions obtained from Varian, Harbor City, Calif., USA.

Example 1 4-(1-Methyl-2-isopropylimidazol-5-yl)-2-{4-[N-(cyclobutyl)sulphamoyl]anilino}pyrimidine

Chlorosulphonic acid (150 μl, 2.16 mmol) was added dropwise to solution of 2-anilino-4-(1-methyl-2-isopropylimidazol-5-yl)pyrimidine (Method 71; 158 mg, 0.54 mmol) in thionyl chloride (3 ml) cooled at 0° C. and the mixture stirred at 0° C. for 10 minutes then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the residue was dried under high vacuum (<2 mmHg) for 1 hour. The resulting solid was placed under nitrogen and a solution of cyclobutylamine (100 μl, 1.08 mmol) and diethylmethylamine (1 ml, 15 mmol) in MeOH (3 ml) added. The mixture was stirred for 30 minutes and the volatiles were evaporated in vacuo. Trituration with water results in a solid which was washed water (3×20 ml) collected by filtration and dried under vacuum at 60° C. to yield the title compound (151 mg, 65%) as a solid. NMR: 1.24 (d, 6H), 1.45 (m, 2H), 1.70 (m, 2H), 1.90 (m, 2H), 3.17 (m, 1H), 3.58 (m, 1H), 3.98 (s, 3H), 7.19 (d, 1H), 7.70 (m, 4H), 7.92 (d, 2H), 8.41 (d, 1), 9.90 (brs, 1H); m/z 427.

Examples 2-23

The following compounds were prepared by the procedure of Example 1 using the appropriate starting materials.

Ex R¹ R² R³ NMR M/z SM  2 1,3 Et Et

1.25 (t, 3H), 1.36 (t, 3H), 1.51 (m, 1H), 1.78 (m, 3H), 2.75 (s, 2H), 3.08 (q, 2H), 3.55 (m, 1H), 3.65 (m, 1H), 3.74 (quin, 1H), 4.76 (q, 2H), 7.39 (d, 1H), 7.55 (br t, 1H), 7.72 (d, 2H), 7.88 (d, 2H), 8.49 (s, 1H), 8.65 (d, 1H), 10.16 (s, 1H) 457 Meth 73  3 1,3 Et Et

1.25 (t, 3H), 1.36 (t, 3H), 2.87 (s, 2H), 3.08 (q, 2H), 3.16 (s, 3H), 3.29 (t, 2H), 4.76 (q, 2H), 7.40 (d, 1H), 7.55 (brs, 1H), 7.73 (d, 2H), 7.88 (d, 2H), 8.51 (s, 1H), 8.65 (d, 1H), 10.16 (s, 1H) 431 Meth 73  4 1,3 Et Et

1.04 (t, 3H), 1.25 (t, 3H), 1.36 (t, 3H), 2.88 (q, 2H), 3.09 (q, 2H), 3.34 (m, 4H), 4.76 (q, 2H), 7.40 (d, 1H), 7.53 (t, 1H), 7.72 (d, 2H), 7.88 (d, 2H), 8.49 (s, 1H), 8.65 (d, 1H), 10.16 (s, 1H) 445 Meth 73  5 1,3 Et Et

1.26 (t, 3H), 1.37 (t, 3H), 1.59 (quintet, 2H), 2.76 (m, 2H), 3.08 (m, 2H), 3.15 (s, 3H), 3.27 (t, 2H), 4.76 (q, 2H), 7.40 (m, 2H), 7.71 (d, 2H), 7.89 (d, 2H), 8.49 (s, 1H), 8.67 (d, 1H), 10.16 (s, 1H) 445 Meth 73  6 1,4 Et MeOCH₂—

1.30 (t, 3H), 1.55 (m, 1H), 1.77 (m, 2H), 1.87 (m, 1H), 2.79 (m, 2H), 3.45 (s, 3H), 3.60 (m, 1H), 3.71 (m, 1H), 3.83 (m, 1H), 4.77 (q, 2H), 4.87 (s, 2H), 7.42 (d, 1H), 7.57 (t, 1H), 7.78 (d, 2H), 7.90 (d, 2H), 8.45 (s, 1H), 8.67 (d, 1H), 10.12 (s, 1H) 473 Meth 72  7 1,4 Et MeOCH₂—

1.05 (t, 3H), 1.28 (t, 3H), 2.88 (m, 2H), 3.35 (q, 4H), 3.43 (s, 3H), 4.77 (q, 2H), 4.88 (s, 2H), 7.40 (d, 1H), 7.52 (brs, 1H), 7.73 (d, 2H), 7.88 (d, 2H), 8.53 (s, 1H), 8.68 (d, 1H), 10.16 (s, 1H) 461 Meth 72  8 1,4 Et MeOCH₂—

1.27 (t, 3H), 1.59 (quintet, 2H), 2.78 (q, 2H), 3.16 (s, 3H), 3.28 (t, 2H), 3.42 (s, 3H), 4.75 (q, 2H), 4.84 (s, 2H), 7.41 (m, 2H), 7.73 (d, 2H), 7.89 (d, 2H), 8.44 (s, 1H), 8.67 (d, 1H), 10.10 (s, 1H) 461 Meth 72  9 1,4 Et MeOCH₂—

1.30 (t, 3H), 2.88 (q, 2H), 3.18 (s, 3H), 3.33 (t, 2H), 3.45 (s, 3H), 4.77 (q, 2H), 4.85 (s, 2H), 7.40 (d, 1H), 7.55 (t, 1H), 7.73 (d, 2H), 7.90 (d, 2H), 8.43 (s, 1H), 8.67 (d, 1H), 10.12 (s, 1H) 447 Meth 72 10 1,2 Me MeOCH₂—

0.07 (m, 2H), 0.35 (m, 2H), 0.80 (m, 1H), 2.63 (t, 2H), 3.30 (s, 3H), 4.02 (s, 3H), 4.55 (s, 2H), 7.25 (d, 1H), 7.50 (t, 1H), 7.70 (m, 3H), 7.90 (d, 2H), 8.48 (d, 1H), 9.95 (s, 1H) 429 Meth 70 11 1,4 Me MeOCH₂—

1.52 (m, 2H), 1.75 (m, 2H), 1.91 (m, 2H), 3.31 (s, 3H), 3.61 (m, 1H), 4.03 (s, 3H), 4.55 (s, 2H), 7.28 (d, 1H), 7.70 (m, 4H), 7.90 (d, 2H), 8.51 (d, 1H), 9.98 (s, 1H) 429 Meth 70 12 i-Pr MeOCH₂—

1.06 (t, 3H), 1.53 (d, 6H), 2.84 (m, 2H), 3.16 (m, 4H), 3.48 (s, 3H), 4.92 (s, 2H), 5.55 (m, 1H), 7.27 (d, 1H), 7.53 (m, 1H), 7.74 (d, 2H), 7.89 (d, 2H), 8.27 (s, 1H), 8.71 (d, 1H), 10.19 (s, 1H) 476 Meth 69 13 1,6 Me i-Pr

1.05 (t, 3H), 1.40 (d, 6H), 2.88 (br q, 2H), 3.33 (m, 4H), 3.55 (br s), 4.19 (s, 3H), 7.41 (d, 1H), 7.57 (br t, 1H), 7.76 (d, 2H), 7.94 (d, 2H), 8.50 (s, 1H), 8.70 (d, 1H), 10.29 (s, 1H) 445 Meth 71 14 1,7 Me i-Pr

1.41 (d, 6H), 3.58 (m, 1H), 3.68 (m, 2H), 4.20 (s, 3H)(not integrated as covered by overlapping exchangeables), 7.42 (d, 1H), 7.80 (d, 2H), 7.99 (d, 2H), 8.48 (t, 1H), 8.49 (s, 1H), 8.70 (d, 1H), 10.30 (s, 1H), 15.00 (v br s, 0.7H) 455 Meth 71 15 1,7 Me i-Pr

1.11 (s, 9H), 1.41 (d, 6H), 3.59 (m, 1H), 4.18 (s, 3H), 7.35 (s, 1H), 7.41 (d, 1H), 7.78 (d, 2H), 7.91 (d, 2H), 8.49 (s, 1H), 8.70 (d, 1H), 10.22 (s, 1H) 429 Meth 71 16 Me Et

1.08 (s, 9H), 1.32 (t, 3H), 3.05 (q, 2H), 4.08 (s, 3H), 7.32 (s, 1H), 7.36 (d, 1H), 7.75 (d, 2H), 7.89 (d, 2H), 8.41 (s, 1H), 8.68 (d, 1H), 10.17 (s, 1H) 415 ⁵ 17 Me c-Pr

1.08 (t, 3H), 1.27 (m, 4H), 2.40 (m, 1H), 2.89 (m, 2H), 3.35 (m, 4H), 4.21 (s, 3H), 7.37 (d, 1H), 7.50 (m, 1H), 7.73 (d, 2H), 7.93 (d, 2H), 8.40 (s, 1H), 8.65 (d, 1H), 10.24 (s, 1H) 443 Meth 79 18 Me c-Pr

1.26 (m, 4H), 2.40 (m, 1H), 2.87 (m, 2H), 3.18 (s, 3H), 3.32 (t, 2H), 4.21 (s, 3H), 7.38 (d, 1H), 7.53 (m, 1H), 7.73 (d, 2H), 7.93 (d, 2H), 8.40 (s, 1H), 8.65 (d, 1H), 10.24 (s, 1H) 429 Meth 79 19 Me c-Pr

1.26 (m, 4H), 1.65 (m, 4H), 2.40 (m, 1H), 2.78 (m, 2H), 3.55 (m, 1H), 3.70 (m, 1H), 3.88 (m, 1H), 4.21 (s, 3H), 7.38 (d, 1H), 7.53 (m, 1H), 7.73 (d, 2H), 7.93 (d, 2H), 8.40 (s, 1H), 8.67 (d, 1H), 10.24 (s, 1H) 455 Meth 79 20 Me c-Pr

0.30 (m, 4H), 1.26 (m, 4H), 1.65 (m, 4H), 2.13 (m, 1H), 2.40 (m, 1H), 4.21 (s, 3H), 7.38 (d, 1H), 7.73 (m, 3H), 7.93 (d, 2H), 8.40 (s, 1H), 8.67 (d, 1H), 10.22 (s, 1H) 411 Meth 79 21 n-Pr c-Pr

0.70 (t, 2H), 1.05 (t, 3H), 1.29 (m, 4H), 1.68 (m, 2H), 2.50 (m, 1H), 2.85 (m, 2H), 3.33 (m, 4H), 4.82 (t, 2H), 7.38 (d, 1H), 7.53 (m, 1H), 7.73 (d, 2H), 7.87 (d, 2H), 8.40 (s, 1H), 8.64 (s, 1H), 10.17 (s, 1H) 471 Meth 80 22 n-Pr c-Pr

0.70 (t, 2H), 1.32 (m, 4H), 1.68 (m, 2H), 2.50 (m, 1H), 2.85 (m, 2H), 3.17 (s, 3H), 3.33 (t, 2H), 4.82 (t, 2H), 7.38 (d, 1H), 7.53 (m, 1H), 7.73 (d, 2H), 7.87 (d, 2H), 8.41 (s, 1H), 8.64 (s, 1H), 10.17 (s, 1H) 457 Meth 80 23 n-Pr c-Pr

0.30 (m, 4H), 0.70 (t, 2H), 1.32 (m, 4H), 1.68 (m, 2H), 2.05 (m, 1H), 2.50 (m, 1H), 3.17 (s, 3H), 4.83 (t, 2H), 7.38 (d, 1H), 7.74 (m, 3H), 7.87 (d, 2H), 8.41 (s, 1H), 8.64 (s, 1H), 10.17 (s, 1H) 439 Meth 80 ¹Isolated as HCl salt ²Purified by flash silica chromatography DCM:MeOH (Polarity increasing from 100:0 to 97:3) ³Purified by Isolute amine column ⁴Purified by Isolute amine column followed by flash silica chromatography DCM:MeOH (Polarity increasing from 100:0 to 97:3) ⁵Example 29 of WO 02/20512 ⁶Ethyldimethylamine used in place of diethylmethylamine. Work-up:- extracted with EtOAc, washed with dilute NaHCO₃, water and brine ⁷Ethyldimethylamine used in place of diethylmethylamine. Product purified by flash silica chromatography DCM:MeOH (96:4)

Example 24 4-(1-Methyl-2-isopropylimidazol-5-yl)-2-{4-[N-(cyclopropyl)sulphamoyl]anilino}pyrimidine

Chlorosulphonic acid (150 μl, 2.16 mmol) was added dropwise to solution of 2-anilino-4-(1-methyl-2-isopropylimidazol-5-yl)pyrimidine (Method 71; 158 mg, 0.54 mmol) in thionyl chloride (3 ml) cooled at 0° C. and the mixture stirred at 0° C. for 10 minutes then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the residue was dried under high vacuum (<2 mmHg) for 1 hour. The resulting solid was placed under nitrogen and a solution of cyclopropylamine (570 μl, 8.1 mmol) in MeOH (3 ml) added. The mixture was stirred for 30 minutes and the volatiles were evaporated in vacuo. Trituration with water results in a solid which was washed water (3×20 ml) collected by filtration and dried under vacuum at 60° C. to yield the title compound (205 mg, 92%) as a solid. NMR: 0.30 (m, 2H), 0.45 (m, 2H), 1.24 (d, 6H), 2.19 (m, 11, 3.17 (m, 1H), 4.01 (s, 3H), 7.19 (d, 1H), 7.70 (d, 2H), 7.92 (d, 2H), 8.02 (m, 1H), 8.50 (d, 1H), 9.90 (brs, 1H); m/z 413.

Examples 25-71

The following compounds were prepared by the procedure of Example 24 using the appropriate starting materials.

Ex R¹ R² R³ NMR M/z SM 25 1,2 i-Pr MeOCH₂—

0.02 (m, 2H), 0.38 (m, 2H), 0.75 (m, 1H), 1.52 (d, 6H), 2.66 (m, 2H), 3.43 (s, 3H), 4.88 (d, 2H), 5.52 (m, 1H), 7.28 (d, 1H), 7.53 (m, 1H), 7.68 (d, 2H), 7.83 (d, 2H), 8.23 (s, 1H), 8.68 (d, 1H), 10.16 (brs, 1H) 457 Meth 69 26 1,2 i-Pr MeOCH₂—

0.32 (m, 2H), 0.53 (m, 2H), 1.52 (d, 6H), 2.07 (m, 1H), 3.47 (s, 3H), 4.92 (d, 2H), 5.52 (m, 1H), 7.28 (d, 1H), 7.74 (m, 3H), 7.83 (d, 2H), 8.21 (s, 1H), 8.68 (d, 1H), 10.20 (brs, 1H) 443 Meth 69 27 1,2 i-Pr MeOCH₂—

1.52 (d, 6H), 2.86 (q, 2H), 3.16 (s, 3H), 3.28 (t, 2H), 3.43 (s, 3H), 4.92 (d, 2H), 5.52 (m, 1H), 7.26 (d, 1H), 7.56 (m, 1H), 7.72 (d, 2H), 7.88 (d, 2H), 8.23 (s, 1H), 8.70 (d, 1H), 10.18 (brs, 1H) 461 Meth 69 28 1,3 Et MeOCH₂—

0.38 (m, 2H), 0.49 (m, 2H), 1.32 (t, 3H), 2.15 (brs, 1H), 3.45 (s, 3H), 4.80 (q, 2H), 4.88 (s, 2H), 7.45 (d, 1H), 7.78 (d, 3H), 7.95 (d, 2H), 8.50 (s, 1H), 8.70 (d, 1H), 10.20 (s, 1H) 429 Meth 72 29 1,4 Et MeOCH₂—

1.10 (s, 9H), 1.27 (t, 3H), 3.43 (s, 3H), 4.78 (q, 2H), 4.86 (s, 2H), 7.33 (s, 1H), 7.40 (d, 1H), 7.76 (d, 2H), 7.86 (d, 2H), 8.49 (s, 1H), 8.69 (d, 1H), 10.11 (s, 1H) 445 Meth 72 30 1,3 Et Et

0.35 (m, 2H), 0.48 (m, 2H), 1.25 (t, 3H), 1.39 (t, 3H), 2.09 (s, 1H), 3.08 (q, 2H), 4.78 (q, 2H), 7.40 (d, 1H), 7.75 (d, 3H), 7.92 (d, 2H), 8.49 (s, 1H), 8.67 (d, 1H), 10.16 (s, 1H) 413 Meth 73 31 1,3 Et Et

1.25 (t, 3H), 1.36 (t, 3H), 3.08 (q, 2H), 3.40 (m, 2H), 4.76 (q, 2H), 5.00 (m, 1H), 5.12 (m, 1H), 5.67 (m, 1H), 7.40 (d, 1H), 7.64 (br t, 1H), 7.73 (d, 2H), 7.88 (d, 2H), 8.49 (s, 1H), 8.65 (d, 1H), 10.16 (s, 1H) 413 Meth 73 32 1,4 Me MeOCH₂—

0.37 (m, 2H), 0.48 (m, 2H), 2.12 (brs, 1H), 3.30 (s, 3H), 4.03 (s, 3H), 4.55 (s, 2H), 7.29 (d, 1H), 7.68 (m, 4H), 7.95 (d, 2H), 8.52 (d, 1H), 10.00 (s, 1H) 415 Meth 70 33⁵ Me t-Bu-(CH₂)₂—

0.98 (s, 9H), 1.60 (m, 2H), 2.78 (m, 2H), 2.89 (q, 2H), 3.18 (s, 3H), 3.30 (m, 2H), 3.99 (s, 3H), 7.20 (d, 1H), 7.44 (t, 1H), 7.63 (s, 1H), 7.70 (d, 2H), 7.93 (d, 2H), 8.43 (d, 1H), 9.90 (s, 1H) 473 Meth 104 34⁵ Me t-Bu-(CH₂)₂—

0.98 (s, 9H), 1.04 (t, 3H), 1.60 (m, 2H), 2.68 (m, 2H), 2.87 (m, 2H), 3.30 (m, 4H), 3.98 (s, 3H), 7.20 (d, 1H), 7.42 (t, 1H), 7.64 (s, 1H), 7.71 (d, 2H), 7.92 (d, 2H), 8.43 (d, 1H), 9.90 (s, 1H) 487 Meth 104 35² Me n-Bu

0.90 (3H, t), 1.04 (3H, t), 1.38 (2H, m), 1.66 (2H, m), 2.74 (2H, t), 2.88 (2H, q), 3.32 (4H, m), 3.98 (3H, s), 7.18 (1H, d), 7.42 (1H, t), 7.71 (2H, d), 7.92 (2H, d), 8.44 (1H, d), 9.90 (1H, s) 459 Meth 89 36² Me n-Bu

0.92 (3H, t), 1.39 (2H, m), 1.68 (2H, m), 2.74 (2H, t), 2.88 (2H, q), 3.16 (3H, s), 3.28 (2H, hidden), 3.96 (3H, s), 7.19 (1H, d), 7.46 (1H, t), 7.64 (1H, s), 7.70 (2H, d), 7.92 (2H, d), 8.42 (1H, d), 9.90 (1H, s) 445 Meth 89 37 i-Pr i-Pr

1.44 (d, 6H), 1.58 (d, 6H), 2.86 (m, 2H), 3.18 (s, 3H), 3.27 (t, 2H), 3.70 (m, 1H), 5.60 (m, 1H), 7.26 (d, 1H), 7.57 (brs, 1H), 7.73 (d, 2H), 7.92 (d, 2H), 8.28 (s, 1H), 8.72 (d, 1H), 10.21 (brs, 1H) 459 Meth 76 38 Me Et

1.04 (t, 3H), 1.36 (t, 3H), 2.88 (m, 2H), 3.04 (q, 2H), 3.34 (m, 4H), 4.12 (s, 3H), 7.38 (d, 1H), 7.57 (brs, 1H), 7.74 (d, 2H), 7.92 (d, 2H), 8.42 (s, 1H), 8.68 (d, 1H), 10.23 (brs, 1H) 431 ⁷ 39 i-Pr i-Pr

1.03 (t, 3H), 1.42 (d, 6H), 1.57 (d, 6H), 2.84 (m, 2H), 3.34 (m, 4H), 3.69 (m, 1H), 5.59 (m, 1H), 7.25 (d, 1H), 7.53 (brs, 1H), 7.72 (d, 2H), 7.89 (d, 2H), 8.26 (s, 1H), 8.72 (d, 1H), 10.19 (brs, 1H) 473 Meth 76 40 Et i-Pr

1.33 (t, 3H), 1.42 (d, 6H), 3.09 (m, 3H), 3.25 (s, 3H), 3.42 (t, 2H), 4.63 (q, 2H), 4.86 (t, 1H), 7.04 (d, 1H), 7.29 (s, 1H), 7.59 (s, 1H), 7.75 (d, 2H), 7.81 (d, 2H), 8.38 (s, 1H) 446 Meth 77 41 Et i-Pr

1.02 (t, 3H), 1.13 (t, 3H), 1.42 (d, 6H), 2.83 (m, 2H), 3.33 (m, 4H), 3.58 (m, 1H), 4.81 (q, 2H), 7.41 (d, 1H), 7.59 (brs, 1H), 7.72 (d, 2H), 7.91 (d, 2H), 8.58 (s, 1H), 8.63 (d, 1H) 460 Meth 77 42⁶ Et MeOCH₂—

1.30 (t, 3H), 3.41 (s, 3H), 3.66 (quintet, 2H), 4.75 (q, 2H), 4.83 (s, 2H), 7.40 (d, 1H), 7.77 (d, 2H), 7.90 (d, 2H), 8.35 (m, 2H), 8.66 (d, 1H), 10.07 (s, 1H) 471 Meth 72 43⁶ Me MeOCH₂—

1.03 (t, 3H), 2.90 (m, 2H), 3.32 (q, 4H), 3.45 (s, 3H), 4.13 (s, 3H), 4.87 (s, 2H), 7.41 (d, 1H), 7.54 (s, 1H), 7.75 (d, 2H), 7.93 (d, 2H), 8.46 (s, 1H), 8.70 (d, 1H), 10.26 (s, 1H) 447 Meth 70 44⁶ i-Pr c-Pr

1.30 (m, 2H), 1.41 (m, 2H), 1.67 (d, 6H), 2.58 (m, 1H), 2.92 (q, 2H), 3.20 (s, 3H), 3.33 (t, 2H), 5.75 (quintet, 1H), 7.31 (d, 1H), 7.60 (t, 1H), 7.79 (d, 2H), 7.91 (d, 2H), 8.20 (s, 1H), 8.73 (d, 1H), 10.23 (s, 1H) 457 Meth 81 45⁶ i-Pr c-Pr

1.09 (t, 3H), 1.35 (m, 2H), 1.41 (m, 2H), 1.67 (d, 6H), 2.57 (m, 1H), 2.91 (q, 2H), 3.38 (m, 4H), 5.71 (quintet, 1H), 7.30 (d, 1H), 7.58 (t, 1H), 7.76 (d, 2H), 7.90 (d, 2H), 8.20 (s, 1H), 8.72 (d, 1H), 10.21 (s, 1H) 471 Meth 81 46⁶ Et c-Pr

1.06 (t, 3H), 1.30 (m, 7H), 2.48 (m, 1H), 2.89 (q, 2H), 3.34 (m, 4H), 4.88 (q, 2H), 7.39 (d, 1H), 7.53 (t, 1H), 7.74 (d, 2H), 7.90 (d, 2H), 8.40 (s, 1H), 8.66 (d, 1H), 10.12 (s, 1H) 457 Meth 82 47⁶ Et c-Pr

1.25 (m, 4H), 1.35 (t, 3H), 2.45 (m, 1H), 2.89 (q, 2H), 3.17 (s, 3H), 3.30 (t, 2H), 4.88 (q, 2H), 7.40 (d, 1H), 7.55 (t, 1H), 7.75 (d, 2H), 7.90 (d, 2H), 8.41 (s, 1H), 8.67 (d, 1H), 10.12 (s, 1H) 443 Meth 82 48 n-Pr MeOCH₂—

(400 MHz) 0.71 (t, 3H), 1.60 (sext, 2H), 2.89 (q, 2H), 3.19 (s, 3H), 3.32 (q, 2H), 3.43 (s, 3H), 4.67 (t, 2H), 4.83 (s, 2H), 7.37 (d, 1H), 7.53 (t, 1H), 7.72 (d, 2H), 7.87 (d, 2H), 8.35 (s, 1H), 8.64 (d, 1H), 10.10 (s, 1H) 461 Meth 75 49 n-Pr MeOCH₂—

(400 MHz) 0.69 (t, 3H), 1.07 (t, 3H), 1.61 (sext, 2H), 2.89 (q, 2H), 3.34 (m, 4H), 3.42 (s, 3H), 4.68 (t, 2H), 4.81 (s, 2H), 7.37 (t, 1H), 7.52 (t, 1H), 7.73 (d, 2H), 7.88 (d, 2H), 8.36 (s, 1H), 8.68 (s, 1H), 10.13 (s, 1H) 475 Meth 75 50⁸ Me n-Pr

0.97 (t, 3H), 1.70 (m, 2H), 2.70 (t, 2H), 2.89 (q, 2H), 3.17 (s, 3H), 3.28 (t, 2H), 3.95 (s, 3H), 7.20 (d, 1H), 7.44 (t, 1H), 7.64 (s, 1H), 7.70 (d, 2H), 7.92 (d, 2H), 8.42 (d, 1H), 9.89 (s, 1H) 431 Meth 91 51⁸ Me n-Pr

0.98 (t, 3H), 1.04 (t, 3H), 1.70 (m, 2H), 2.70 (t, 2H), 2.86 (q, 2H), 3.31 (m, 4H), 3.97 (s, 3H), 7.19 (d, 1H), 7.44 (t, 1H), 7.64 (s, 1H), 7.70 (d, 2H), 7.92 (d, 1H), 8.42 (d, 1H), 9.90 (s, 1H) 445 Meth 91 52⁹ Me MeO(CH₂)₂—

3.05 (t, 2H), 3.15 (q, 2H), 3.29 (s, 3H), 3.38 (s, 3H), 3.44 (t, 2H), 3.84 (t, 2H), 4.0 (s, 3H), 4.92 (t, 1H), 7.02 (d, 1H), 7.41 (br s, 1H), 7.59 (s, 1H), 7.80 (m, 4H), 8.40 (d, 1H) 447 Meth 92 53⁹ Me MeO(CH₂)₂—

1.15 (t, 3H), 3.05 (t, 2H), 3.14 (q, 2H), 3.38 (s, 3H), 3.44 (m, 4H), 3.84 (t, 2H), 3.98 (s, 3H), 5.01 (t, 1H), 7.04 (d, 1H), 7.50 (br s, 1H), 7.80 (m, 4H), 8.40 (d, 1H) 461 Meth 92 54 Et n-Pr

0.98 (t, 3H), 1.19 (t, 3H), 1.75 (q, 2H), 2.69 (t, 2H), 2.88 (q, 2H), 3.30 (t, 2H), 4.59 (m, 2H), 7.22 (d, 1H), 7.46 (t, 1H), 7.74 (m, 3H), 7.88 (d, 2H), 8.42 (d, 1H), 9.83 (s, 1H) 445 Meth 93 55 Et n-Pr

0.98 (t, 3H), 1.06 (t, 3H), 1.19 (t, 3H), 1.74 (m, 2H), 2.70 (t, 2H), 2.88 (q, 2H), 3.36 (m, 4H), 4.59 (m, 2H), 7.22 (d, 1H), 7.44 (t, 1H), 7.70 (m, 3H), 7.88 (d, 2H), 8.42 (d, 1H), 9.82 (s, 1H) 458 Meth 93 56 Et n-Bu

0.97 (t, 3H), 1.18 (t, 3H), 1.40 (m, 2H), 1.70 (m, 2H), 2.72 (t, 2H), 2.88 (q, 2H), 3.17 (s, 3H), 3.27 (t, 2H), 4.59 (q, 2H), 7.21 (d, 1H), 7.44 (t, 1H), 7.70 (s, 1H), 7.72 (d, 2H), 8.42 (d, 1H), 9.81 (s, 1H) 458 Meth 94 57 Et n-Bu

0.92 (t, 3H), 1.06 (t, 3H), 1.18 (t, 3H), 1.38 (m, 2H), 1.69 (m, 2H), 2.74 (t, 2H), 2.88 (q, 2H), 3.37 (m, 2H), 4.58 (q, 2H), 7.20 (d, 1H), 7.43 (t, 1H), 7.68 (s, 1H), 7.70 (d, 2H), 7.84 (d, 2H), 8.42 (d, 1H), 9.82 (s, 1H) 473 Meth 94 58⁸ i-Pr n-Pr

1.0 (t, 1H), 1.48 (d, 6H), 1.79 (m, 2H), 2.78 (t, 2H), 2.86 (m, 2H), 3.30 (t, 2H), 5.59 (m, 1H), 7.15 (d, 1H), 7.45 (m, 2H), 7.78 (d, 2H), 7.88 (d, 2H), 8.44 (d, 1H), 9.86 (s, 1H) 459 Meth 95 59⁸ i-Pr n-Pr

1.0 (m, 6H), 1.48 (d, 6H), 1.78 (m, 2H), 2.77 (t, 2H), 2.85 (q, 2H), 3.32 (m, 4H), 5.58 (m, 1H), 7.16 (d, 1H), 7.44 (m, 2H), 7.69 (d, 2H), 7.88 (d, 2H), 8.45 (d, 1H), 9.85 (s, 1H) 473 Meth 95 60⁸ i-Pr Et

1.28 (t, 3H), 2.48 (d, 6H), 2.86 (m, 4H), 3.29 (t, 2H), 5.59 (m, 1H), 7.15 (d, 1H), 7.44 (m, 2H), 7.70 (d, 2H), 7.86 (d, 2H), 8.45 (d, 1H), 9.84 (s, 1H) 445 Meth 96 61⁸ i-Pr Et

1.04 (t, 3H), 1.28 (t, 3H), 1.46 (d, 6H), 2.82 (m, 4H), 3.35 (m, 4H), 5.59 (m, 1H), 7.15 (d, 1H), 7.24 (m, 2H), 7.69 (d, 2H), 7.86 (d, 2H), 8.43 (d, 1H), 9.85 (s, 1H) 459 Meth 96 62 i-Pr EtOCH₂—

1.20 (t, 3H), 1.52 (d, 6H), 2.86 (m, 2H), 3.15 (s, 3H), 3.29 (t, 2H), 3.63 (m, 2H), 4.92 (s, 2H), 5.52 (m, 1H), 7.27 (d, 1H), 7.53 (t, 1H), 7.71 (d, 2H), 7.87 (d, 2H), 8.22 (s, 1H), 8.70 (d, 1H), 10.16 (s, 1H) 475 Meth 78 63 Me i-PrCH₂—

0.96 (d, 6H), 2.15-2.08 (m, 1H), 2.61 (d, 2H), 2.88 (q, 2H), 3.18 (s, 3H), 3.30-3.25 (m, 2H), 3.98 (s, 3H), 7.20 (d, 1H), 7.44 (t, 1H), 7.64 (s, 1H), 7.72 (d, 2H), 7.92 (d, 2H), 8.42 (d, 1H), 9.90 (s, 1H) 445 Meth 109 64 Me i-PrCH₂—

0.95 (d, 6H), 1.03 (t, 3H), 2.15-2.07 (m, 1H), 2.30 (d, 2H), 2.88 (q, 2H), 3.18 (d, 2H), 3.38-3.30 (m, 2H), 3.98 (s, 3H), 7.20 (d, 1H), 7.43 (t, 1H), 7.73-7.64 (m, 3H), 7.90 (d, 2H), 8.42 (d, 1H), 9.90 (s, 1H) 459 Meth 109 65 n-Pr n-Pr

0.62 (t, 3H), 1.0 (t, 3H), 1.51 (q, 2H), 1.75 (q, 2H), 2.70 (t, 2H), 2.89 (q, 2H), 3.18 (s, 3H), 3.30-3.25 (m, 2H), 4.52 (t, 2H), 7.20 (d, 1H), 7.48 (t, 1H), 7.74-7.65 (m, 3H), 7.88 (d, 2H), 8.42 (d, 1H), 9.82 (s, 1H) 459 Meth 99 66 n-Pr n-Pr

0.68 (t, 3H), 0.99 (t, 3H), 1.04 (t, 3H), 1.50 (q, 2H), 1.6 (q, 2H), 2.70 (t, 2H), 2.92-2.85 (m, 2H), 3.39-3.28 (m, 2H), 4.51 (t, 2H), 7.20 (d, 2H), 7.43 (t, 1H), 7.68 (s, 1H), 7.70 (d, 2H), 7.88 (d, 2H), 8.42 (d, 1H), 9.82 (s, 1H) 473 Meth 99 67 n-Pr t-Bu(CH₂)₂—

0.70 (t, 3H), 0.98 (s, 9H), 1.46-1.64 (m, 4H), 2.62-2.72 (m, 2H), 2.87 (q, 2H), 3.18 (s, 3H), 3.27-3.30 (m, 2H), 4.53 (t, 2H), 7.20 (d, 1H), 7.48 (t, 1H), 7.63 (s, 1H), 7.71 (4 2H), 7.87 (d, 2H), 8.42 (s, 1H), 9.82 (s, 1H) 501 Meth 115 68 Et n-Pr

0.96 (t, 3H), 1.17 (t, 3H), 1.73 (m, 2H), 2.69 (t, 2H), 2.77 (q, 2H), 3.35 (q, 2H), 4.59 (m, 3H), 7.21 (d, 1H), 7.34 (t, 1H), 7.69 (m, 3H), 7.89 (d, 2H), 8.41 (d, 1H), 9.81 (s, 1H) 431 Meth 93 69 Et n-Pr NH₂ 0.98 (t, 3H), 1.25 (t, 3H), 1.80 (m, 2H), 3.06 (t, 2H), 4.78 (q, 2H), 7.09 (br s, 4H), 7.39 (d, 1H), 7.75 (d, 2H), 7.86 (d, 2H), 8.51 (s, 1H), 8.64 (d, 1H), 10.14 (s, 1H) 387 Meth 93 70¹⁰ n-Pr Me₂NCH₂—

0.68 (t, 3H), 1.54 (q, 2H), 2.18 (s, 6H), 2.89 (q, 2H), 3.17 (s, 3H), 3.30 (m, 2H), 3.53 (s, 2H), 4.59 (t, 2H), 7.22 (d, 1H), 7.43 (t, 1H), 7.66 (s, 1H), 7.77 (d, 2H), 7.84 (d, 2H), 8.44 (d, 1H), 9.84 (s, 1H) 474 Meth 119 71¹⁰ n-Pr EtNHCH₂—

0.68 (t, 3H), 1.05 (t, 3H), 1.51 (m, 2H), 2.57 (m, 2ff), 2.88 (m, 2H), 3.18 (s, 3H), 3.28 (m, 2H), 3.80 (s, 2H), 4.59 (t, 2H), 7.20 (d, 1H), 7.50 (s, 1H), 7.68 (s, 1H) 7.70 (d, 2H), 7.88 (d, 2H), 8.43 (d, 1H), 9.85 (s, 1H) 474 Meth 120 ¹Isolated as HCl salt ²Purified by flash silica chromatography DCM:MeOH (Polarity increasing from 100:0 to 97:3) ³Purified by Isolute amine column ⁴Purified by Isolute amine column followed by flash silica chromatography DCM:MeOH (Polarity increasing from 100:0 to 97:3) ⁵Purified by flash silica chromatography DCM:MeOH (95:5) ⁶Purified by Isolute amine column followed by flash silica chromatography DCM:MeOH (Polarity increasing from 100:0 to 97:3) and isolated as the HCl salt ⁷Example 29 of WO 02/20512 ⁸Purified by flash silica chromatography DCM:MeOH (98:2) ⁹Purified by flash silica chromatography DCM:MeOH (98.5:1.5) ¹⁰Purified by chromatography on silica gel eluting with DCM:MeOH (90:10)

Example 72 4-[1-(Methoxypropyl-2-yl)-2-(methoxyethyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl) sulphamoyl]anilino}pyrimidine

To a stirred solution of 2-amino-4-(1-methoxyisopropyl-2-methoxymethylimidazol-5-yl)pyrimidine (Method 85; 163 mg, 0.6 mmol), N-(2-ethoxyethyl)-4-iodobenzenesulphonamide (Method 1; 400 mg, 1.2 mmol), tris(dibenzylideneacetone) dipalladium (0) (35 mg, 0.038 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (47 mg, 0.076 mmol) in dioxane (10 ml) was added sodium t-butoxide (258 mg, 2.69 mmol) and the mixture heated at 80° C. overnight. The reaction was cooled to room temperature and MeOH (5 ml) was added and the mixture poured onto an Isolute SCX-2 column, eluted first with MeOH (10×30 ml) and the product was then eluted with 5% methanolic ammonia (10×30 ml). The solvent was removed by evaporation and the residue purified by flash chromatography on silica gel eluting with DCM/MeOH (100:0 increasing in polarity to 97:3) to yield a foam which was dissolved in MeOH (2 ml) and treated with 1N HCl in ether (350 μl, 0.35 mmol) for 5 minutes. Solvent was evaporated in vacuo to yield a yellow foam which was triturated with ether to yield after filtration the title compound as a yellow solid (63 mg, 20%) NMR: 1.02 (t, 3H), 1.54 (d, 3H), 2.87 (m, 2H), 3.14 (s, 3H), 3.30 (m, 4H), 3.43 (s, 3H), 3.55 (m, 1H), 3.75 (m, 1H), 4.90 (s, 2H), 5.65 (m, 1H), 7.26 (d, 1H), 7.54 (m, 1H), 7.71 (d, 2H), 7.88 (d, 2H), 8.26 (s, 1H), 8.70 (d, 1H), 10.20 (brs, 1H); m/z 505.

Examples 73-74

The following compounds were prepared by the procedure of Example 72 using the appropriate starting materials.

Ex R¹ NMR M/z SM 73

1.37 (t, 3H), 3.06 (q, 2H), 3.62 (m, 2H), 4.12 (s, 3H), 7.39 (d, 1H), 7.77 (d, 1H), 7.94 (d, 1H), 8.42 (s, 1H), 8.44 (t, 1H), 8.65 (d, 1H), 10.28 (brs, 1H) 441 Meth 86 Meth  2 74

1.35 (t, 3H), 1.58 (m, 2H), 2.76 (m, 2H), 3.04 (q, 2H), 3.17 (s, 3H), 3.24 (t, 2H), 4.10 (s, 3H), 7.37 (d, 1H), 7.39 (t, 1H), 7.71 (d, 1H), 7.92 (d, 1H), 8.39 (s, 1H), 8.66 (d, 1H), 10.21 (brs, 1H) 431 Meth 86 Meth  3

Example 75 2-{4-[N-(2-Methoxyethyl)sulphamoyl]anilino}-4-[1-methyl-2-(2-methyl-2-hydroxypropyl)imidazol-5-yl]pyrimidine

The title compound was prepared by the procedure of Method 89 using Example 35 of WO 02/20512 and acetone as the starting materials. NMR: 1.20 (s, 6H), 2.88-2.83 (m, 4H), 3.18-3.15 (m, 5H), 4.0 (s, 3H), 4.78 (s, 1H), 7.20 (d, 1H), 7.44 (t, 1H), 7.70-7.67 (m, 3H), 7.90 (d, 2H), 8.46 (d, 1H), 9.90 (s, 1H); m/z 461.

Example 76 4-[2-(Prop-1-enyl)-1-(isopropyl)imidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine

n-Butyl lithium (656 μl of a 1.6 N solution in hexane, 1.05 mmol), was added dropwise to a solution of ethyl triphenylphosphonium iodide (437 mg, 1.05 mmol), in anhydrous THF (15 ml), under nitrogen at 0° C. A solution of 4-(2-formyl-1-isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine (Method 105; 300 mg, 0.523 mmol), in THP (5 ml), was then slowly added. The mixture was allowed to warm to ambient temperature and stirred for 18 hours. The volatiles were removed by evaporation and the residue dissolved in EtOAc (40 ml), washed with water (2×15 ml), brine (15 ml), and dried. The solvent removed by evaporation to give a crude product (254 mg), as a yellow foam. The crude product was purified by chromatography on silica-gel eluting with 3% MeOH in DCM), the semi-pure product (70 mg), was dissolved in TFA/H₂O (1:1, 10 ml), and stirred for 1 hour. The TFA was removed by evaporation, the resulting aqueous solution neutralised with saturated NaHCO₃, and the product extracted with DCM (3×5 ml). The extracts were combined, dried and the solvent removed. The residue was purified by preparative reverse phase HPLC, eluting with acetonitrile/H₂O, 0.01% formic buffer. Pure fractions were neutralised with 2N aqueous sodium hydroxide solution. The resulting white precipitate, was collected by filtration and dried to give the title compound (1:2.5 mixture of E:Z isomers), as a white solid (5 mg, 2%). NMR: Z isomer 1.51 (d, 61), 2.09 (d, 31), 2.92 (t, 2H), 3.17 (s, 3H), 3.33 (t, 2H), 5.60 (m, 1H), 6.05 (m, 1H), 6.51 (m, 1H), 7.1 (br s, 1H), 7.16 (d, 1H), 7.57 (s, 1H), 7.71 (d, 2H), 7.88 (d, 2H), 8.48 (d, 1H), 9.47 (s, 1H); E isomer 1.51 (d, 6H), 1.94 (d, 3H), 2.92 (t, 2H), 3.17 (s, 3H), 3.33 (t, 2H), 5.60 (m, 1H), 6.60 (m, 1H), 6.67 (m, 1H), 7.1 (br s, 1H), 7.13 (d, 1H), 7.47 (s, 1H), 7.71 (d, 2H), 7.88 (d, 2H), 8.44 (d, 1H), 9.47 (s, 1H); m/z: 457.

Example 77 4-[2-(2-Methylprop-1-enyl)-1-ethylimidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine

Aqueous TFA (90%) was added to a mixture of 4-[2-(2-methylprop-1-enyl)-1-ethylimidazol-5-yl]-2-(4-[N-(2-methoxyethyl)-N-t-butylsulphamoyl]anilino}pyrimidine (Method 111; 70 mg, 0.14 mmol), and anisole (90 μl, 0.83 mmol), and the mixture stirred at ambient temperature for 1 hour. The volatiles were evaporated and the residue dissolved in water. The solution was neutralised (NaHCO₃), and extracted with EtOAc. The extracts were dried, and the solvent evaporated to give the title compound (30 mg, 41%). NMR: 1.19 (t, 3H), 1.99 (s, 3H), 2.15 (s, 3H), 2.89 (q, 2H), 3.18 (s, 3H), 3.30-3.28 (m, 2), 4.65 (q, 2H), 6.28 (s, 1H), 7.25 (d, 1H), 7.50 (t, 1H), 7.70 (d, 2H), 7.85 (s, 1H), 7.89 (d, 2H), 8.45 (d, 1H), 9.85 (s, 1H); m/z: 457.

Example 78 4-[2-(2-Methylprop-1-enyl)-1-methylimidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine

2-{4-[N-(2-Methoxyethyl)sulphamoyl]anilino}4-[t-methyl-2-(2-methyl-2-hydroxypropyl)imidazol-5-yl]pyrimidine (Example 75), was treated by the procedure described in Method 110 to give the title compound (30 mg, 14%). NMR: 1.99 (s, 3H), 2.15 (s, 3H), 2.87 (q, 2H), 3.18 (s, 3H), 3.23-3.30 (m, 2H), 4.0 (s, 31), 6.26 (s, 1), 7.22 (d, 1H), 7.43 (t, 1H), 7.70 (d, 2H), 7.79 (s, 1H), 7.92 (d, 2H), 8.44 (d, 1H), 9.90 (s, 1H); m/z: 443.

Example 79 4-[2-(But-3-en-1-yl)-1-propylimidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine

A mixture of caesium fluoride (180 mg, 1.2 mmole), and 4-(2-(but-3-enyl)-1-propylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine (Method 100; 100 mg, 0.17 mmol), in DMF (3 ml), was heated at 140° C. under nitrogen for 24 hours. The mixture was diluted with water and extracted with EtOAc. The extracts were washed with water and brine, dried, and the solvent evaporated. The residue was purified by chromatography on silica gel eluting with EtOAc to give the title compound. (8 mg, 10%). NMR: 0.7 (t, 3H), 1.52 (q, 2H), 2.80 (t, 2), 2.85-2.89 (m, 2H), 3.19 (s, 3H), 3.18-3.22 (m, 2H), 3.30 (t, 2H), 4.52 (t, 2H), 4.98 (d, 1H), 5.10 (dd, 1H), 5.95-5.89 (m, 1H), 7.20 (d, 1H), 7.44 (t, 1H), 7.70 (s, 3H), 7.74 (d, 2H), 7.89 (d, 2H), 8.45 (d, 1H), 9.80 (s, 1H); m/z: 471.

Example 80 4-[2-(Methylthiomethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine

Sodium thiomethoxide (21 mg, 0.3 mmol) was added to a stirred solution of 4-[2-(chloromethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine (Method 116; 52 mg, 0.1 mmol) in MeOH (5 ml) and the solution was stirred at ambient temperature for 3 hour. The solvent was removed evaporation and the residue was partitioned between water and EtOAc. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried (Na₂SO₄) and the volatiles removed by evaporation. The residue was triturated with ether and collected by filtration. This solid was suspended in MeOH (2 ml) and 1.0M ethereal hydrogen chloride was added to give a clear solution. The volatiles were removed by evaporation and the residue triturated with ether giving the title compound (42 mg, 80%) as the hydrochloride salt. NMR: 0.72 (t, 3H), 1.06 (t, 3H), 1.63 (m, 2H), 2.18 (s, 3H), 2.88 (q, 2H), 3.35 (m, 4H), 4.42 (s, 2H), 4.72 (m, 2H), 7.37 (d, 1H), 7.54 (t, 1H), 7.75 (d, 2H), 7.89 (d, 2H), 8.39 (s, 1H), 8.68 (d, 1H), 10.14 (s, 1H); m/z 491.

Examples 81-82

The following compounds were prepared by the procedure of Example 80 using 4-[2-(chloromethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine (Method 116) and the appropriate reagent but without conversion of the free base product to hydrochloride salt. M/z Ex Compound NMR [MH]+ 81 4-[2-(Isopropylthiomethyl)-1- 0.67(t, 3H), 1.03(t, 3H), 1.20(d, 6H), 519 (propyl)imidazol-5-yl]-2-{4- 1.55(m, 2H), 2.85(m, 2H), 2.93(m, 1H), [N-(2-ethoxyethyl)sulphamoyl] 3.33(m, 4H), 3.94(s, 2H), 4.55(t, 2H), anilino}pyrimidine 7.21(d, 1H), 7.45(t, 1H), 7.68(s, 1H), 7.72(d, 2H), 7.84(d, 2H), 8.45(d, 1H), 9.85(s, 1H) 82 4-[2-(Ethylthiomethyl)-1- 0.68(t, 3H), 1.04(t, 3H), 1.17(t, 3H), 505 (propyl)imidazol-5-yl]-2-{4- 1.55(m, 2H), 2.53(m, 2H), 2.86(q, 2H), [N-(2-ethoxyethyl)sulphamoyl] 3.33(m, 4H), 3.90(s, 2H), 4.55(t, 2H), 7.21(d, anilino}pyrimidine 1H), 7.45(t, 1H), 7.68(s, 1H), 7.72(d, 2H), 7.84(d, 2H), 8.45(d, 1H), 9.85(s, 1H)

Example 83 4-[2-(Ethylsulphinlmethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine

A solution of sodium periodate (43 mg, 0.2 mmol) in water (0.5 ml) was added to a stirred solution of 4-[2-(ethylthiomethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine (Example 82; 70 mg, 0.14 mmol) in MeOH (2 ml) and the solution was stirred for 18 hours. The MeOH was removed by evaporation and the aqueous residue was extracted with EtOAc. The extracts were combined, washed with brine, dried and the volatiles removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (95:5 increasing in polarity to 90:10) and the purified product triturated with ether to give the title compound (37 mg, 51%). NMR: 0.68 (t, 3H), 1.05 (t, 3H), 1.22 (t, 3H), 1.52 (m, 2H), 2.85 (m, 4H), 3.33 (m, 4H), 4.31 (d of d, 2H), 4.63 (m, 2H), 7.23 (d, 1H), 7.46 (t, 1H), 7.70 (d, 2H), 7.78 (s, 1H), 7.86 (d, 2H), 8.48 (d, 1H), 9.90 (s, 1H); m/z 521.

Example 84 4-[2-(Ethylsulphonylmethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine

Oxone (123 mg, 0.2 mmol) was added to a stirred solution of 4-[2-(ethylthiomethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine (Example 82; 70 mg, 0.14 mmol) in MeOH/acetone/water (15:5:3) (2 ml) at 0-4° C. The solution was allowed to warm to ambient temperature and stirred for 2 hr. The reaction mixture was diluted with water and extracted with EtOAc. The extracts were combined, washed with brine, dried (Na₂SO₄) and the volatiles removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (95:5) and the purified product triturated with ether to give the title compound (44 mg, 59%). NMR: 0.65 (t, 3H), 1.03 (t, 3H), 1.27 (t, 3H), 1.52 (m, 2H), 2.85 (q, 2H), 3.30 (m, 6H), 4.64 (t, 2H), 4 81 (s, 2H), 7.25 (d, 1H), 7.46 (t, 1H), 7.70 (d, 2H), 7.79 (s, 1H), 7.97 (d, 2H), 8.50 (d, 1H), 9.91 (s, 1H); m/z 537.

Example 85 4-[2-(Isopropoxymethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine

Sodium isopropoxide (87 mg, 1.05 mmol) was added to a stirred suspension of 4-[2-(chloromethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine (Method 116; 100 mg, 0.21 mmol) in isopropanol (20 ml). The reaction was stirred for 48 hours at ambient temperature, and was then poured into water (80 ml) and extracted with EtOAc (3×30 ml). The extracts were combined washed with brine (2×40 ml), dried and the volatiles removed by evaporation. The residue was purified by reverse phase HLPC (C18 column) eluting with aqueous ammonia/water/acetonitrile (5:90:5 decreasing in polarity to (5:0:95) to give the title compound (18 mg, 17%) as a brown gum. M/z 503.

Example 86 4-[2-(Phenethyl)-1-(methyl)imidazol-5-yl]-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine

4-{2-[2-(4-Chlorophenyl)ethyl]-1-(methyl)imidazol-5-yl}-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine (Method 117; 115 mg, 0.219 mmol) and triethylamine (34 μl, 0.241 mmol) was dissolved in ethanol (20 ml) and EtOAc (10 ml) and 30% palladium on charcoal catalyst (30 mg) added. The mixture was stirred for 3 days under an atmosphere of hydrogen. The catalyst was removed by filtration and filtrate evaporated. The residue was dissolved in DCM (20 ml), washed with water (2×5 ml), dried and the solvent removed by evaporation to give the title compound (67 mg, 63%) as a white solid. NMR: 2.88 (q, 2H) 3.05 (s, 4H) 3.16 (s, 3H) 3.28 (t, 3H) 3.90 (s, 3H) 7.21 (d, 1H) 7.28 (m, 5H) 7.69 (s, 1H) 7.70 (d, 2H) 8.44 (d, 1H) 9.94 (s, 1H); m/z 493.

Preparation of Starting Materials

The starting materials for the examples above are either commercially available or are readily prepared by standard methods from known materials. For example, the following reactions are an illustration, but not a limitation, of some of the starting materials used in the above reactions.

Method 1 N-(2-Ethoxyethyl)₄-iodobenzenesulphonamide

2-Ethoxyethylamine (2.14 g, 24 mmol) and diisopropylethylamine (4.2 ml, 24 mmol) were dissolved in DCM (50 ml) and cooled to 0° C. To this was added pipsyl chloride (6.05 g, 20 mmol) in portions and the reaction stirred for 18 hours. Volatiles were evaporated in vacuo. The residue was dissolved in EtOAc (50 ml), extracted 1N citric acid (2×50 ml), brine (50 ml), dried and evaporated in vacuo to yield an oil which solidified on standing to give the title compound as a pale yellow solid (6.97 g, 98%). NMR: 1.01 (t, 3H), 2.89 (q, 2), 3.30 (m, 4H), 7.53 (d, 21, 7.75 (t, 1H), 7.97 (d, 2H); m/z 354 (M-H)⁻.

Methods 2-5

The following compounds were prepared by the procedure of Method 1 using the appropriate starting materials. Meth Compound NMR M/z 2 N-(2,2,2-trifluoroethyl)-4- 3.69(q, 2H), 7.58(d, 2H), 7.93(d, 2H), 364(M−H)⁻ iodosulphonamide 8.65(brs, 1H) 3 N-(3-Methoxypropyl)-4- 1.68(m, 2H), 3.02(q, 2H), 3.21(s, 3H), 3.38(t, 356 iodobenzenesulphonamide 2H), 5.10(s, 1H), 7.51(d, 2H), 7.80(d, 2H) 4 N-(2-Methoxyethyl)-4- 3.14(q, 2H), 3.25(s, 3H), 3.40(q, 2H), 4.97(s, 342 iodobenzenesulphonamide 1H), 7.58(d, 2H), 7.90(d, 2H) 5 N-t-Butyl-4- 1.08(s, 9H), 7.56(m, 3H), 7.94(d, 2H) 338[MH]⁻ iodobenzenesulphonamide

Methods 6-7

The following compounds were synthesised by the procedure as described in JOC 1987, 2714-2716. Meth Compound 6 5-Methyl-4-(methylamino)isoxazole hydrochloride 7 5-Acetyl-1-methyl-2-(methoxymethyl)imidazole

Methods 8-49

The following compounds were prepared using procedures analogous to those described in JOC 1987, 2714-2726. Meth Compound NMR M/z SM 8 5-Methyl-4-(N- 1.09(t, 3H), 2.08(q, 2H), 169 Meth 6 methyl-N- 2.38(s, 3H), 3.16(s, 3H), propionylamino) 8.16(s, 1H) isoxazole 9 1-Methyl-2-ethyl-5- 1.36(t, 3H), 2.41(s, 3H), 153 Meth 8 acetylimidazole 2.72(q, 2H), 3.82(s, 3H), 7.72(s, 1H) 10 4-(Isopropylamino)-5- (CDCl₃) 1.12(d, 6H), 141 4-Amino-5- methylisoxazole 2.30(s, 3H), 3.21(1H, sept), methylisoxazole 8.01(s, 1H) hydrochloride 11 5-Methyl-4-(N- 0.95(d, 6H), 2.35(s, 3H), 213 Meth 10 isopropyl-N- 3.20(s, 3H), 3.60(s, 2H), methoxyacetamido) 4.70(m, 1H), 8.60(s, 1H) isoxazole 12 1-isopropyl-2- 1.43(d, 6H), 2.40(s, 3H), 197 Meth 11 methoxymethyl-5- 3.24(s, 3H), 4.50(s, 2H), acetylimidazole 4.90(m, 1H), 7.92(s, 1H) 13 5-Methyl-4-(N- 1.03(d, 6H), 2.36(s, 3H), 183 Meth 6 methyl-N- 2.48(m, 1H), 3.16(s, 3H), isobutyrylamino) 8.20(s, 1H) isoxazole 14 1-Methyl-2-isopropyl- 1.36(d, 6H), 2.42(s, 3H), 167 Meth 13 5-acetylimidazole 3.10(m, 1H), 3.84(s, 3H), 7.75(s, 1H) 15 5-Methyl-4-(N- 2.00(s, 3H), 2.34(s, 3H), 141 4-Amino-5- acetamido)isoxazole 8.64(s, 1H), 9.60(brs, 1H) methylisoxazole hydrochloride 16 5-Methyl-4- 1.21(t, 3H), 2.58(s, 3H), 127 Meth 15 (ethylamino)isoxazole 3.22(q, 2H), 8.76(s, 1H) hydrochloride 17 5-Methyl-4-(N-ethyl- (CDCl₃) 1.12(t, 3H), 2.39(s, 199 Meth 16 N-methoxyacetamido) 3H), 3.36(s, 3H), 3.64(q, isoxazole 2H), 3.75(s, 2H), 8.16(s, 1H) 18 5-Acetyl-1-ethyl-2- (CDCl₃) 1.37(t, 3H), 2.48(s, 183 Meth 17 methoxymethyl 3H), 3.38(s, 3H), 4.39(q, imidazole 2H), 4.56(s, 2H), 7.74(s, 1H) 19 5-Methyl-4-(N-ethyl- (CDCl₃) 1.11(q, 6H), 183 5-Methyl-4- N-propylamido) 2.05(q, 2H), 2.39(s, 3H), 3.65(q, (ethylamino)isoxazole isoxazole 2H) 8.16(s, 1H) hydrochloride 20 5-Acetyl-1,2- (CDCl₃) 1.35(m, 6H), 167 Meth 19 diethylimidazole 2.45(s, 3H), 2.73(q, 2H), 4.30(q, 2H), 7.73(s, 1H) 21 5-Methyl-4- 1.01(d, 3H), 2.06(s, 3H), 171 4-Amino-5- (methoxyisopropyl 3.05(m, 2H), 3.19(m, 6H), methylisoxazole amino)isoxazole 2.92(m, 1H), 8.26(s, 1H) hydrochloride hydrochloride 22 5-Methyl-4-(N- 0.90(d, 3H), 2.35(s, 3H), 243 Meth 21 methoxyisopropyl-N- 3.20(m, 8H), 3.60(s, 2H), methoxyacetamido) 4.80(m, 1H), 8.40(m, 1H) isoxazole 23 5-Acetyl-1- 1.38(d, 3H), 2.40(s, 3H), 227 Meth 22 methoxyisopropyl-2- 3.16(s, 3H), 3.24(s, 3H), methoxymethyl 3.58(m, 1H), 3.78(m, 1H), imidazole 4.50(q, 2H), 4.96(m, 1H), 7.97(s, 1H) 24 5-Methyl-4-(N- 0.81(t, 3H), 1.37(sext, 2H), 213 Meth 45 propyl-N- 2.34(s, 3H), 3.18(s, 3H), methoxyacetamido) 3.42(t, 2H), 3.71(s, 2H), isoxazole 8.65(s, 1H) 25 1-Propyl-2- 0.83(t, 3H), 1.62(sext, 2H), 197 Meth 24 methoxymethyl-5- 2.40(s, 3H), 3.25(s, 3H), acetylimidazole 4.18(t, 2H), 4.50(s, 2H), 7.90(s, 1H) 26 5-Methyl-4-(N- 1.02(br m, 12H), 2.32(m, 211 Meth 10 isopropyl-N-2- 1H), 2.37(s, 3H), 4.98(m, methylpropylamido)isoxazole 1H), 8.14(s, 1H) 27 1-Isopropyl-2- 1.38(d, 6H), 1.55(d, 6H), 195 Meth 26 isopropyl-5- 2.43(s, 3H), 3.17(m, 1H), acetylimidazole 5.18(m, 1H), 7.78(s, 1H) 28 5-Methyl-4-[N-ethyl- 1.04(d, 6H), 1.08(t, 3H), 197 Meth 16 N-(2-methylpropyl 2.38(s, 3H), 2.41(m, 1H), amido)]isoxazole 3.60(q, 2H), 8.15(s, 1H) 29 1-Ethyl-2-isopropyl-5- 1.32(t, 3H), 1.34(d, 6H), 182 Meth 28 acetylimidazole 2.42(s, 3H), 3.01(m, 1H), 4.36(q, 2H), 7.77(s, 1H) 30 5-Methyl-4-(N- 1.0(m, 9H), 2.34(s, 3H), Meth 10 isopropyl-N- 3.34(m, 2H), 3.61(s, 2H), ethoxyacetamido) 4.73(m, 1H), 8.58(s, 1H) isoxazole 31 1-Isopropyl-2- 1.10(t, 3H), 1.43(d, 6H), Meth 30 ethoxymethyl-5- 2.43(s, 3H), 3.44(m, 2H), acetylimidazole 4.57(s, 2H), 4.96(m, 1H), 7.91(s, 1H) 32 5-Methyl-4-(N- 0.76(m, 4H), 1.42(m, 1H), 181 5-Methyl-4- methyl-N- 2.36(s, 3H), 3.07(s, 3H), (methylamino)isoxazole cyclopropylamido) 8.78(s, 1H) hydrochloride isoxazole 33 1-Methyl-2- 0.60(m, 4H), 1.72(m, 1H), 165 Meth 32 cyclopropyl-5- 2.00(s, 3H), 3.55(s, 3H), acetylimidazole 7.41(s, 1H) 34 5-Methyl-4-(N- 0.80(m, 7H), 1.35(m, 3H), 209 Meth 45 propyl-N- 2.32(s, 3H), 3.45(t, 2H), cyclopropylamido) 8.76(s, 1H) isoxazole 35 1-Propyl-2- 0.80(m, 7H), 1.65(m, 2H), 193 Meth 34 cyclopropyl-5- 2.05(m, 1H), 2.38(s, 3H), acetylimidazole 4.35(t, 2H), 7.80(s, 1H) 36 5-Methyl-4-(N- 0.61(br s, 2H), 0.76(br s, 209 Meth 10 isopropyl-N- 2H), 0.97(br s, 6H), cyclopropylamido) 1.24(m, 1H), 2.36(s, 3H), isoxazole 4.76(m, 1H), 8.66(s, 1H) 37 1-Isopropyl-2- 0.96(m, 4H), 1.49(d, 6H), 193 Meth 36 cyclopropyl-5- 2.11(m, 1H), 2.37(s, 3H), acetylimidazole 5.40(m, 1H), 7.77(s, 1H) 38 5-Methyl-4-(N-ethyl- 0.70(m, 4H), 1.00(t, 3H), 195 Meth 16 N-cyclopropylamido) 1.36(m, 1H), 2.38(s, 3H), isoxazole 3.54(q, 2H), 8.74(s, 1H) 39 1-Ethyl-2- 0.86(m, 2H), 0.97(m, 2H), 179 Meth 38 cyclopropyl-5- 1.23(t, 3H), 2.04(m, 1H), acetylimidazole 2.36(s, 3H), 4.39(q, 2H), 7.78(s, 1H) 40 5-Methyl-4-(N- 0.81(t, 3H), 1.37(m, 2H), 183 Meth 45 propyl-N-acetamido) 1.75(s, 3H), 2.34(s, 3H), isoxazole 3.42(t, 2H), 8.67(s, 1H) 41 1-Propyl-2-methyl-5- 0.83(t, 3H), 1.60(m, 2H), 167 Meth 40 acetylimidazole 2.37(m, 6H), 4.17(t, 2H), 7.83(s, 1H) 42 5-Methyl-4-(N- Used crude Meth 10 isopropylformido)isoxazole 43 5-Acetyl-1- 1.38(d, 6H), 2.48(s, 3H), 153 Meth 42 isopropylimidazole 5.13(q, 2H), 7.86(s, 1H), 8.10(s, 1H) 44 5-Methyl-4-(N- 1.05(t, 3H), 2.28(q, 2H), 153[MH]− 4-amino-5- propylamido)isoxazole 2.35(s, 3H), 8.65(s, 1H), methylisoxazole 9.50(s, 1H) hydrochloride 45 5-Methyl-4- 0.90(t, 3H), 1.62(m, 2H), 141 Meth 44 (propylamino)isoxazole 2.53(s, 3H), 3.10(t, 2H), 8.68(s, 1H) 46 5-Methyl-4-(N- 1.05(t, 3H), 2.28(q, 2H), 153[MH]− 4-amino-5- propionylamido)isoxazole 2.35(s, 3H), 8.65(s, 1H), methylisoxazole 9.50(s, 1H) hydrochloride 47 5-Methyl-4- 0.90(t, 3H), 1.62(m, 2H), 141 Meth 46 (propylamino)isoxazole 2.53(s, 3H), 3.10(t, 2H), 8.68(s, 1H) 48 5-Methyl-4-(N- 0.82(m, 3H), 1.42(m, 2H), 167[MH]− Meth 47 propylformido)isoxazole 2.28 & 2.38(s, 3H), 3.50(m, 2H), 8.08 & 8.23(2s, 1H), 8.62 & 8.72(s, 1H) 49 5-Acetyl-1- 0.76(t, 3H), 1.63(m, 2H), 153 Meth 48 propylimidazole 2.40(s, 3H), 4.28(t, 2H), 7.90(s, 1H), 7.95(s, 1H)

Method 50 5-(3-Dimethylaminoprop-2-en-1-oyl)-1-isopropyl-2-methoxymethylimidazole

1-Isopropyl-2-methoxymethyl-5-acetylimidazole (Method 12; 3.34 g, 17 mmol) was dissolved in a mixture of DMF (34 ml) and DMP.DEA (11.5 ml, 68 mmol) and the mixture heated under reflux, under an atmosphere of nitrogen, for 18 hours. The volatiles were removed by evaporation. A solid was precipitated with ether, collected by filtration and air dried to yield the title compound as a brown solid (2.25 g, 53%); NMR 1.43 (d, 61), 2.95 (m, 6H), 3.20 (s, 3H), 4.46 (s, 2H), 5.00 (m, 1H), 5.56 (d, 1H), 7.55 (m, 2H); m/z 252.

Methods 51-68

The following compounds were prepared by the procedure of Method 50. Meth Compound NMR M/z SM  51¹ 5-(3-Dimethylaminoprop-2-en-1- 2.87(s, 3H), 3.05(s, 3H), 224 Meth 7 oyl)-1-methyl-2- 3.20(s, 3H), 3.83(s, 3H), 4.45(s, methoxymethylimidazole 2H), 5.58(d, 1H), 7.55(d, 1H), 7.59(s, 1H)  52² 5-(3-Dimethylaminoprop-2-en-1- 1.20(t, 3H), 2.62(q, 2H), 208 Meth 9 oyl)-1-methyl-2-ethylimidazole 2.95(s, 6H), 3.78(s, 3H), 5.56(d, 1H), 7.51(m, 2H)  53¹ 5-(3-Dimethylaminoprop-2-en-1- 1.20(d, 6H), 3.05(m, 1H), 222 Meth oyl)-1-methyl-2-isopropylimidazole 3.80(s, 3H), 5.53(d, 1H), 14 7.50(m, 2H) 54 5-(3-Dimethylaminoprop-2-en-1- 1.23(t, 3H), 2.96(m, 6H), 222 Meth oyl)-1-ethyl-2- 3.25(s, 3H), 4.36(q, 2H), 18 methoxymethylimidazole 4.47(s, 2H), 5.60(d, 1H), 7.56(d, 1H), 7.63(s, 1H) 55 5-(3-Dimethylaminoprop-2-en-1- 1.20(m, 6H), 2.65(q, 2H), 238 Meth oyl)-1,2-diethylimidazole 2.96(brs, 6H), 4.31(q, 2H), 20 5.57(d, 1H), 7.51(d, 1H), 7.57(s, 1H) 56 5-(3-Dimethylaminoprop-2-en-1- 1.40(d, 3H), 2.95(m, 6H), 282 Meth oyl)-1-methoxyisopropyl-2- 3.16(s, 3H), 3.24(s, 3H), 23 methoxymethylimidazole 3.63(m, 1H), 3.89(m, 1H), 4.47(q, 2H), 5.00(m, 1H), 5.58(d, 1H), 7.75(m, 2H) 57 5-(3-Dimethylaminoprop-2-en-1- 2.26(s, 3H), 2.95(brs, 6H), 194 ³ oyl)-1,2-dimethylimidazole 3.8(s, 3H), 5.56(d, 1H), 7.52(m, 2H) 58 5-(3-Dimethylaminoprop-2-en-1- 0.82(t, 3H), 1.62(sext, 2H), 252 Meth oyl)-1-propyl-2- 2.7-3.3(br m, 6H), 3.24(s, 25 methoxymethylimidazole 3H), 4.25(t, 2H), 4.45(s, 2H), 5.60(d, 1H), 7.56(d, 1H), 7.60(s, 1H) 59 5-(3-Dimethylaminoprop-2-en-1- 1.37(d, 6H), 1.58(d, 6H), 250 Meth oyl)-1-isopropyl-2- 2.94(s, 6H), 3.16(m, 1H), 27 isopropylimidazole 5.23(m, 1H), 5.53(d, 1H), 7.50(s, 1H), 7.62(d, 1H) 60 5-(3-Dimethylaminoprop-2-en-1- 1.19(t, 3H), 1.21(d, 6H), 237 Meth oyl)-1-ethyl-2-isopropylimidazole 2.48(s, 6H), 3.03(m, 1H), 4.33(q, 29 2H), 5.57(d, 1H), 7.55(d, 1H), 7.57(s, 1H) 61 5-(3-Dimethylaminoprop-2-en-1- 1.10(t, 3H), 1.28(d, 6H), 266 Meth oyl)-1-isopropyl-2- 2.99(m, 6H), 3.41(m, 2H), 4.52(s, 31 ethoxymethylimidazole 2H), 5.51(m, 1H), 5.59(d, 1H), 7.58(d, 2H) 62 5-(3-Dimethylaminoprop-2-en-1- 0.83(m, 2H), 0.94(m, 2H), Meth oyl)-1-methyl-2- 1.97(m, 1H), 2.95(br s, 6H), 33 cyclopropylimidazole 3.91(s, 3H), 5.55(d, 1H), 7.50(m, 2H) 63 5-(3-Dimethylaminoprop-2-en-1- 0.80(m, 7H), 1.65(m, 2H), 248 Meth oyl)-1-propyl-2- 1.95(m, 1H), 2.95(br s, 6H), 35 cyclopropylimidazole 4.40(t, 2H), 5.55(d, 2H), 7.50(m, 2H) 64 5-(3-Dimethylaminoprop-2-en-1- 0.91(m, 4H), 1.49(d, 6H), 248 Meth oyl)-1-isopropyl-2- 2.04(m, 1H), 2.93(m, 6H), 37 cyclopropylimidazole 5.51(m, 2H), 7.40(s, 1H), 7.51(d, 1H) 65 5-(3-Dimethylaminoprop-2-en-1- 0.88(m, 4H), 1.24(t, 3H), 234 Meth oyl)-1-ethyl-2- 1.99(m, 1H), 2.94(br s, 6H), 39 cyclopropylimidazole 4.47(q, 2H), 5.53(d, 1H), 7.51(m, 2H) 66 5-(3-Dimethylaminoprop-2-en-1- 0.82(t, 3H), 1.60(m, 2H), 222 Meth oyl)-1-propyl-2-methylimidazole 2.32(s, 3H), 2.95(br s, 6H), 41 4.25(t, 2H), 5.58(d, 1H), (7.54d, 1H), 7.57(s, 1H) 67 5-(3-Dimethylaminoprop-2-en-1- 1.43(d, 6H), 2.95(m, 6H), Meth oyl)-1-isopropylimidazole 5.32(m, 1H), 5.58(d, 1H), 43 7.60(m, 2H), 7.90(s, 1H) 68 5-(3-Dimethylaminoprop-2-en-1- 0.75(t, 3H), 1.65(m, 2H), 208 Meth oyl)-1-propylimidazole 2.95(br s, 6H), 4.25(t, 2H), 49 5.62(d, 1H), 7.55(d, 1H), 7.64(s, 1H), 7.66(s, 1H) ¹DMF:DMF.DMA(1:1) used as solvent. Purified by flash chromatography on silica gel eluting with DCM/2% methanolic ammonia(100:0 increasing in polarity to 95:5). ²DMF.DMA used as solvent ³Starting material(2-methyl-4-acetylimidazole) was synthesized according to Tetrahedron letters 1985, 26(29), 3423-3426.

Method 69 2-Anilino-4-(1-isopropyl-2-methoxymethylimidazol-5-yl)pyrimidine

5-(3-Dimethylaminoprop-2-en-1-oyl)-1-isopropyl-2-methoxymethylimidazole (Method 50; 1.26 g, 5 mmol), phenylguanidine hydrogen carbonate (1.09 g, 5.5 mmol) and sodium methoxide (594 mg, 11 mmol) were suspended in anhydrous DMA (10 ml) and the mixture heated at 110° C. for 3 hours. The volatiles were evaporated in vacuo the residues was suspended in water (50 ml). The solution was extracted DCM (3×50 ml). The combined extracts were washed with water (50 ml) and then brine (50 ml), dried and the volatiles removed by evaporation. The residue was purified by flash silica chromatography eluting with DCM:MeOH (100:0 increasing in polarity to 97:3) to give the title compound as brown oil. NMR: 1.43 (d, 6H), 3.30 (s, 3H), 4.56 (s, 2H), 5.54 (m, 1H), 6.96 (t, 1H), 7.05 (d, 1H), 7.24 (t, 2H), 7.44 (s, 1H), 7.65 (d, 2), 8.41 (d, 1H), 9.42 (s, 1H); m/z 324.

Methods 70-84

The following compounds were prepared by the procedure of Method 69. Meth Compound NMR M/z SM 70 2-Anilino-4-(1-methyl-2- 3.30(s, 3H) 3.99(s, 3H), 296 Meth methoxymethylimidazol-5-yl) 4.50(s, 2H), 6.94(t, 1H), 7.13(d, 51 pyrimidine 1H), 7.28(t, 2H), 7.65(s, 1H), 7.69(d, 2H), 8.41(d, 1H), 9.48(s, 1H) 71 2-Anilino-4-(1-methyl-2- 1.36(d, 6H), 3.08(m, 1H), 294 Meth isopropylimidazol-5-yl)pyrimidine 3.96(s, 3H), 6.94(d, 1H), 53 7.05(t, 1H), 7.19(s, 1H), 7.37(t, 2H), 7.53(s, 1H), 7.58(d, 2H), 8.36(d, 1H) 72 2-Anilino-4-(1-ethyl-2- 1.17(t, 3H), 3.28(s, 3H), 310 Meth methoxymethylimidazol-5- 4.51(s, 2H), 4.60(q, 2H), 6.97(t, 54 yl)pyrimidine 1H), 7.16(d, 1H), 7.29(t, 2H), 7.64(d, 2H), 7.71(s, 1H), 8.40(d, 1H), 9.40(s, 1H) 73 2-Anilino-4-(1,2-diethylimidazol- 1.15(t, 3H), 1.27(t, 3H), 294 Meth 5-yl)pyrimidine 2.72(q, 2H), 4.53(q, 2H), 6.96(t, 55 1H), 7.11(d, 1H), 7.28(t, 2H), 7.64(m, 3H), 8.33(d, 1H), 9.34(s, 1H) 74 2-Anilino-4-(1,2-dimethylimidazol- 2.37(s, 3H), 3.93(s, 3H), 266 Meth 5-yl)pyrimidine 6.95(t, 1H), 7.08(d, 1H), 7.28(t, 57 2H), 7.59(s, 1H), 7.69(d, 2H), 8.35(d, 1H), 9.43(s, 1H) 75 2-Anilino-4-(1-propyl-2- (400MHz), 0.67(t, 3H), 324 Meth methoxymethylimidazol-5- 1.53(sext, 2H), 3.30(s, 3H), 58 yl)pyrimidine 4.54(m, 4H), 7.00(t, 1H), 7.15(d, 1H), 7.32(t, 2H), 7.64(d, 2H), 7.70(s, 1H), 8.42(d, 1H), 9.43(s, 1H) 76 2-Anilino-4-(1-isopropyl-2- 1.23(d, 6H), 1.43(d, 6H), 323 Meth isopropylimidazol-5-yl)pyrimidine 3.22(m, 1H), 5.61(m, 1H), 59 6.96(t, 1H), 7.01(d, 1H), 7.26(t, 2H), 7.42(s, 1H), 7.64(d, 2H), 8.38(d, 1H), 9.39(br s, 1H) 77 2-Anilino-4-(1-ethyl-2- 1.23(t, 3H), 1.38(d, 6H), 309 Meth isopropylimidazol-5-yl)pyrimidine 3.05(m, 1H), 4.50(q, 2H), 6.94(d, 60 1H), 7.06(t, 1H), 7.34(t, 2H), 7.56(d, 2H), 7.58(s, 1H), 8.32(d, 1H) 78 2-Anilino-4-(1-isopropyl-2- 1.12(t, 3H), 1.46(d, 6H), 338 Meth ethoxymethylimidazol-5- 3.49(m, 2H), 4.58(s, 2H), 5.54(m, 61 yl)pyrimidine 1H), 6.97(t, 1H), 7.06(d, 1H), 7.28(t, 2H), 7.45(s, 1H), 7.66(d, 2H), 8.42(d, 1H), 9.43(s, 1H) 79 2-Anilino-4-(1-methyl-2- 0.83(m, 2H), 0.94(m, 2H), 292 Meth cyclopropylimidazol-5- 2.08(m, 1H), 4.04(s, 3H), 62 yl)pyrimidine 6.93(t, 1H), 7.09(d, 1H), 7.27(t, 2H), 7.51(s, 1H), 7.70(d, 2H), 8.38(d, 1H), 9.40(s, 1H) 80 2-Anilino-4-(1-propyl-2- 0.70(t, 3H), 0.90(m, 4H), 320 Meth cyclopropylimidazol-5- 1.55(m, 2H), 2.06(m, 1H), 63 yl)pyrimidine 4.63(t, 2H), 6.93(t, 1H), 7.06(d, 1H), 7.27(t, 2H), 7.56(s, 1H), 7.70(d, 2H), 8.32(d, 1H), 9.35(s, 1H) 81 2-Anilino-4-(1-isopropyl-2- 0.96(m, 4H), 1.53(d, 6H), 320 Meth cyclopropylimidazol-5- 2.13(m, 1H), 5.80(m, 1H), 64 yl)pyrimidine 6.99(m, 2H), 7.28(t, 2H), 7.37(s, 1H), 7.67(d, 2H), 8.36(d, 1H), 9.40(s, 1H) 82 2-Anilino-4-(1-ethyl-2- 0.92(m, 4H), 1.23(t, 3H), 306 Meth cyclopropylimidazol-5- 2.07(m, 1H), 4.69(q, 2H), 65 yl)pyrimidine 6.98(t, 1H), 7.08(d, 1H), 7.29(t, 2H), 7.57(s, 1H), 7.65(d, 2H), 8.33(d, 1H), 9.33(s, 1H) 83 2-Anilino-4-(1-propyl-2- 0.66(t, 3H), 1.51(m, 2H), 294 Meth methylimidazol-5-yl)pyrimidine 2.39(s, 3H), 4.49(t, 2H), 66 6.99(t, 1H), 7.09(d, 1H), 7.62(s, 1H), 7.65(d, 2H), 8.36(d, 1H), 9.38(s, 1H) 84 2-Anilino-4-(1-propylimidazol-5- 0.68(t, 3H), 1.55(m, 2H), 280 Meth yl)pyrimidine 4.48(t, 2H), 6.97(t, 1H), 68 7.14(d, 1H), 7.30(t, 2H), 7.63(d, 2H), 7.73(s, 1H), 7.88(s, 1H), 8.38(d, 1H), 9.40(s, 1H)

Method 85 2-Amino-4-(1-methoxyisopropyl-2-methoxymethylimidazol-5-yl)pyrimidine

5-(3-Dimethylaminoprop-2-en-1-oyl)-1-methoxyisopropyl-2-methoxymethylimidazole (Method 56; 3.13, 11.1 mmol) and guanidine hydrochloride (2.65 g, 27.8 mmol) were suspended in 1-butanol (20 ml). Sodium methoxide (2.4 g, 44 mmol) was added in one portion and the mixture heated under reflux, under an atmosphere of nitrogen, for 18 hours. The volatiles were removed by evaporation. Water (50 ml) was added and extracted EtOAc (3×50 ml). The organic layers were combined and dried with Chemelut CE1010 and the solvent evaporated in vacuo. The residue was purified by flash silica chromatography eluting with DCM:MeOH (100:0 increasing in polarity to 95:5) to give the title compound as an orange solid (1.86 g, 60%). NMR: 1.43 (d, 3H), 3.16 (s, 3H), 3.24 (s, 3M), 3.63 (m, 1H), 3.89 (m, 1H), 4.50 (q, 2H), 5.26 (m, 1H), 6.57 (s, 2H), 6.80 (d, 1), 7.40 (s, 1H), 8.21 (d, 1H); m/z 278.

Methods 86-88

The following compounds were prepared by the procedure of Method 85. Meth Compound NMR M/z SM 86 2-Amino-4-(1-methyl-2- 1.21(t, 3H), 2.69(q, 2H), 203 Meth ethylimidazol-5-yl)pyrimidine 3.92(s, 3H), 6.52(brs, 2H), 6.81(d, 52 1H), 7.48(s, 1H), 8.15(d, 1H) 87 2-Amino-4-(1-propyl-2- 0.82(t, 3H), 1.59(q, 2H), 218 Meth methylimidazol-5-yl)pyrimidine 2.38(s, 3H), 4.42(t, 2H), 6.45(s, 66 2H), 6.82(d, 1H), 7.50(s, 1H), 8.20(d, 1H) 88 2-Amino-4-(1- 1.53(d, 6H), 5.05(s, 2H), 204 Meth isopropylimidazol-5- 5.59(sept, 1H), 6.85(d, 1H), 7.56(s, 67 yl)pyrimidine 1H), 7.78(s, 1H), 8.23(d, 1H)

Method 89 2-Anilino-4-(1-methyl-2-n-butylimidazol-5-yl)pyrimidine

2-Anilino-4-(1,2-dimethylimidazol-5-yl)pyrimidine (Method 74; 2 g, 7.55 mmol) was dissolved in anhydrous THF (100 ml) at RT under a nitrogen atmosphere. The stirring solution was cooled using dry-ice/acetone bath to −70° C. A 1.6M solution of n-butyl lithium in hexane (6.3 ml, 10.08 mmol) was added drop-wise keeping temperature <−60° C. until the dark red colour remained. One more equivalent of n-butyl lithium in hexane (4.7 ml, 7.55 mmol), was then added dropwise keeping the temperature below −60° C. At this point the solution stirred at −70° C. for 10 minutes when propyl iodide (809 μl, 8.29 mmol) was added, the temperature was maintained at −70° C. for an additional 10 minutes then allowed to rise to RT. The reaction was allowed to stir for 1 hr at room temperature when water (100 ml) was added. The aqueous layer extracted with EtOAc (2×20 ml). Organics were combined, dried solvent evaporated in vacuo. The residue was purified by flash silica chromatography DCM:MeOH (95:5) to yield the title compound (1.03 g, 45%) as a pure white solid NMR: 0.90 (t, 3H), 1.39 (m, 2H), 1.66 (m, 2H), 2.70 (t, 2H), 3.94 (s, 3H), 6.95 (t, 1H), 7.08 (d, 1H), 7.28 (t, 2H, 7.65 (d, 2H), 7.59 (s, 1H), 8.35 (d, 1H), 9.42 (s, 1H); m/z 308.

Methods 90-102

The following compounds were prepared by the procedure of Method 89. Meth Compound NMR M/z SM  90 2-Anilino-4-[1-methyl-2-(2- 0.9(s, 3H), 2.65(m, 1H), 352 Pivaldehyde hydroxy-3,3-dimethylbutyl) 2.84(m, 1H), 3.60(m, 1H), imidazol-5-yl]pyrimidine 3.98(s, 3H), 4.83(d, 1H), 6.97(t, 1H), 7.10(d, 1H), 7.28(dd, 2H), 7.63(s, 1H), 7.71(d, 2H), 8.38(d, 1H), 9.45(d, 1H)  91 2-Anilino-4-(1-methyl-2- 0.95(t, 3H), 1.70(m, 2H), 294 Ethyl Iodide + Meth propylimidazol-5- 2.68(t, 2H), 3.92(s, 3H), 74 yl)pyrimidine 6.95(t, 1H), 7.08(d, 1H), 7.28(t, 2H), 7.60(s, 1H), 7.69(d, 2H), 8.34(d, 1H), 9.44(s, 1H)  92 2-Anilino-4-[1-methyl-2-(2- 2.96(t, 2H), 3.26(s, 3H), 309 Chloromethyl- methoxyethyl)imidazol-5- 3.70(t, 2H), 3.95(s, 3H), methylether + Meth yl]pyrimidine 6.94(t, 1H), 7.09(s, 1H), 74 7.26(t, 2H), 7.60(s, 1H), 7.74(d, 2H), 8.38(s, 1H), 9.44(s, 1H)  93 2-Anilino-4-(1-ethyl-2- 0.96(t, 3H), 1.15(t, 3H), 308 Ethyl Iodide + Ex propylimidazol-5- 1.70(m, 2H), 2.68(t, 2H), 28 yl)pyrimidine 4.54(q, 2H), 6.97(t, 1H), WO 7.10(d, 1H), 7.29(t, 2H), 02/20512 7.65(m, 3H), 8.34(d, 1H), 9.35(s, 1H)  94 2-Anilino-4-(1-ethyl-2- 0.92(t, 3H), 1.14(t, 3H), 322 Propyl butylimidazol-5- 1.38(m, 2H), 1.68(m, 2H), Iodide + Ex yl)pyrimidine 2.70(t, 2H), 4.56(q, 2H), 28 6.98(t, 1H), 7.08(d, 1H), WO 7.26(t, 2H), 7.64(m, 3H), 02/20512 8.37(d, 1H), 9.36(s, 1H)  95 2-Anilino-4-(1-isopropyl-2- 1.98(t, 3H), 1.4(d, 6H), 322 Ethyl Iodide + Ex propylimidazol-5- 1.78(m, 2H), 2.76(t, 2H), 32 yl)pyrimidine 5.62(m, 1H), 6.97(t, 1H), WO 7.02(d, 1H), 7.30(t, 2H), 02/20512 7.44(s, 1H), 7.66(d, 2H), 8.39(d, 1H), 9.40(s, 1H)  96 2-Anilino-4-(1-isopropyl-2- 1.26(t, 3H), 1.44(d, 6H), 308 Methyl ethylimidazol-5- 2.80(q, 2H), 5.62(m, 1H), Iodide + Ex yl)pyrimidine 6.97(t, 1H), 7.02(d, 1H), 32 7.26(t, 2H), 7.42(s, 1H), WO 7.64(s, 2H), 8.39(d, 1H), 02/20512 9.39(s, 1H)  97 2-Anilino-4-(1-methyl-2-(2- No NMR data 324 Acetone + Ex methyl-2- 5 WO hydroxypropyl)imidazol-5- 02/20512 yl)pyrimidine  98 2-{4-[N-(2-methoxyethyl)- 1.22-1.10(m, 18H), 2.82(s, 531 Acetone + Meth N-(t-butyl)sulphamoyl] 2H), 3.28(s, 3H), 3.55-3.42(m, 107 anilino}-4-(1-ethyl-2-(2- 4H), 4.79(q, 2H), methyl-2-hydroxypropyl) 4.94(s, 1H), 7.22(d, 1H), 7.75-7.70(m, imidazol-5-yl)pyrimidine 3H), 7.88(d, 2H), 8.42(d, 1H), 9.88(s, 1H).  99 2-Anilino-4-(1,2-dipropyl- No NMR data 322 Ethyl iodide + Meth imidazol-5-yl)pyrimidine 83 100 4-(2-But-3-enyl-1- No NMR data 601 Allyl propylimidazol-5-yl)-2-{4- bromide + Meth [N-(2-methoxyethyl)-N-(2- 108 trimethylsilylethoxymethyl), sulphamoyl]anilino}pyrimidine  101¹ 4-[2-(3,3-Dimethyl-2- 0.64(t, 3H), 0.97(s, 9H), 380 Pivaldehyde + Meth hydroxybut-1-yl)-1- 1.58-1.42(m, 2H), 3.59(s, 83 (propyl)imidazol-5-yl]-2- 1H), 4.52-4.41(m, 1H), anilinopyrimidine 4.63-4.58(m, 1H), 4.90(s, 1H), 6.99(t, 1H), 7.10(d, 1H), 7.30(t, 2H), 7.63-7.60(m, 3H), 8.39(d, 2H), 9.39(s, 1H).  102¹ 4-{2-[2-(4- 3.02(s, 4H), 3.90(s, 3H), 390 4- Chlorophenyl)ethyl]-1- 6.97(t, 1H), 7.09(d, 1H), chlorobenzyl (methyl)imidazol-5-yl}-2- 7.30(m, 6H), 7.64(s, 1H), bromide + Meth anilinopyrimidine 7.70(d, 2H), 8.38(d, 1H), 74 9.42(s, 1H) ¹Purified by chromatography on silica eluting with 2% MeOH/EtOAc

Method 103 2-Anilino-4-(1-methyl-2-(3,3-dimethylbut-1-enylimidazol-5-yl)pyrimidine

2-Anilino-4-[1-methyl-2-(2-hydroxy-3,3-dimethylbutyl)imidazol-5-yl]pyrimidine (Method 90; 988 mg, 2.8 mmol) was dissolved in DCM (20 ml). To this was added triethylamine (1.18 ml, 8.4 mmol) followed by methanesulphonyl chloride (458 μl, 5.92 mmol) in portions. After 18 hr the volatiles were evaporated in vacuo and the residue resuspended in toluene (20 ml). To this stirred solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene(4 ml, 26.7 mmol) and heated to reflux for 1 hr. Volatiles evaporated in vacuo and the residue was triturated with water. The resultant solid was collected by filtration, washed water (20 ml) and dried under vacuum at 60° C. to yield the title compound (830 mg, 90%). NMR 1.15 (s, 9H), 4.04 (s, 3H), 6.38 (d, 1H), 6.8 (d, 1H), 6.96 (t, 1H), 7.12 (d, 1H), 7.28 (t, 2H), 7.71 (m, 3H), 8.38 (d, 1H), 9.48 (s, 1H); m/z 334.

Method 104 2-Anilino-4-[1-methyl-2-(3,3-dimethylbutylimidazol-5-yl]pyrimidine

To a solution of 2-anilino-4-(1-methyl-2-(3,3-dimethylbut-1-enylimidazol-5-yl)pyrimidine (Method 103; 200 mg, 0.6 mmol) in EtOH (20 ml) was added 10% Pd/C (100 mg) and stirred under a hydrogen atmosphere for 3 days. The reaction mixture was passed through a pad of celite to remove the catalyst and the filtrate evaporated in vacuo. The residue was triturated with ether to give the title compound 105 mg (53%). NMR 0.97 (s, 9H), 1.60 (m, 2H), 2.67 (m, 2H), 3.97 (s, 3H), 6.98 (t, 1H), 7.08 (d, 1H), 7.27 (dd, 2H), 7.60 (s, 1H), 7.70 (d, 2H), 8.39 (d, 1H), 9.42 (s, 1H); m/z 336.

Method 105 4-(2-Formyl-1-isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxmethyl)sulphamoyl]anilino}pyrimidine

4-(1-Isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine (Method 106; 1.22 g, 2.33 mmol), was dissolved in anhydrous THF (70 ml), under nitrogen. The solution was cooled to −78° C. and n-butyl lithium (3.48 ml of a 1.6 N solution in hexanes, 5.57 mmol), was added slowly, maintaining the temperature at less than −65° C. The reaction mixture was then stirred at −78° C. for 30 minutes, then DMF (345 μl, 4.46 mmol), was added and mixture allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was then poured into water (10 ml), and extracted with EtOAc (2×50 ml). The organic extracts were combined, washed with water (50 ml), brine (50 ml), and dried. The volatiles were removed and the residue was purified by chromatography on silica gel eluting with 3% MeOH in DCM, to give the title product, (307 mg, 24%), as a pale yellow foam. NMR: 0.02 (s, 9H), 0.83 (dd, 2H), 1.63 (d, 6H), 3.28 (s, 3H), 3.37 (t, 2H), 3.42 (dd, 2H), 3.52 (t, 2H), 4.78 (s, 2H), 5.71 (m, 1H), 7.40 (d, 1H), 7.82 (d, 2H), 7.92 (s, 1H), 8.01 (d, 2H), 8.78 (d, 1H), 9.91 (s, 1H); m/z: 573 [MH]⁻.

Method 106 4-(1-Isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl) sulphamoyl]anilino}pyrimidine

Sodium t-butoxide (1.42 g, 14.78 mmol), was added to a stirred solution of 2-amino-4-(1-isopropylimidazol-5-yl)pyrimidine (Method 88; 2.0 g, 9.85 mmol), N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl-4-iodobenzenesulphonamide (Method 112; 5.11 g, 10.84 mmol), tris(dibenzylideneacetone), dipalladium (0), (650 mg, 0.71 mmol), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (470 mg, 0.75 mmol), in dioxane (180 ml), and the mixture heated at 80° C. overnight. The reaction was cooled to ambient temperature and acetic acid (282 μl, 4.93 mmol), added. The reaction mixture was poured into water (70 ml), and extracted with EtOAc (3×40 ml). The organic extracts were combined, washed with water (2×40 ml), saturated brine (40 ml), dried, and the solvent removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with DCM/MeOH (97:3), and then by chromatography on silica gel eluting with DCM/MeOH (98.5:1.5), to yield the title compound (1.95 g, 36%). NMR: 0.01 (s, 9H), 085 (dd, 2H), 1.53 (d, 6H), 3.26 (s, 21), 3.37 (t, 2H), 3.44 (dd, 2H), 3.52 (t, 1H), 4.79 (s, 2H), 5.57 (m, 1H), 7.36 (d, 1H), 8.80 (m, 3H), 7.98 (d, 21), 8.19 (s, 1H), 8.58 (d, 1H), 10.13 (s, 1H); m/z: 545 [MH]⁻.

Methods 107-108

The following compounds were prepared by an analogous procedure to Method 106. Meth Compound NMR M/z SM 107 4-(1-Ethyl-2- 1.15-1.22(m, 12H), 2.40(s, 3H), 473 Meth 27 methylimidazol-5-yl)-2- 3.24-3.28(m, 3H), 3.46-3.55(m, WO {4-[N-(2-methoxyethyl)- 4H), 4.59(q, 2H), 7.20(d, 1H), 02/20512 + Meth N-t-butylsulphamoyl] 7.68(s, 1H), 7.70(d, 2H), 7.89(d, 113 anilino}pyrimidine 2H), 8.42(d, 1H), 9.84(s, 1H) 108 4-(2-Methyl-1- No NMR data 559 Meth 87 + Meth propylimidazol-5-yl)-2- [MH]⁻ 112 {4-[N-(2-methoxyethyl)- N-(2-trimethylsilylethoxy methyl), sulphamoyl] anilino}pyrimidine

Method 109 4-(1-Methyl-2-(2-methylpropyl)imidazol-5-yl)-2-anilinopyrimidine

4-(1-Methyl-2-(2-methylprop-1-enyl)imidazol-5-yl)-2-anilinopyrimidine (method 110; 400 mg, 1.3 mmol), and 10% Pd on C catalyst (150 mg), in ethanol (50 ml), was hydrogenated at 40 C and 20 bar for 18 hours. The catalyst was removed by filtration and the filter pad washed with ethanol. The solvent was evaporated and the residue triturated with ether and collected by filtration to give the title compound (280 mg, 71%). M/z: 308.

Method 110 4-(1-Methyl-2-(2-methylprop-1-enyl)imidazol-5-yl)-2-anilinopyrimidine

Methanesulphonyl chloride (151 μl, 1.96 mmol), was added to a solution of 2-anilino-4-(1-methyl-2-(2-methyl-2-hydroxypropyl)imidazol-5-yl)pyrimidine (Method 97; 600 mg, 1.86 mmol), and triethylamine (777 μl, 5.58 mmol), in DCM (10 ml), at ambient temperature under nitrogen. The mixture was stirred for 3 hours then adsorbed directly onto silica gel and purified by chromatography eluting with EtOAc to give the title compound (235 mg, 42%). NMR: 1.98 (s, 3H), 2.14 (s, 3H), 3.99 (s, 3H), 6.24 (s, 1H), 6.98 (t, 1H), 7.10 (d, 1H), 7.28 (dd, 2H, 7.69-7.72 (m, 3H), 8.40 (d, 1H), 9.42 (s, 1H); m/z: 306.

Method 111

The following compounds were prepared by an analogous procedure to Method 110. Meth Compound M/z SM 111 4-[2-(2-Methylprop-1-enyl)-1-ethylimidazol-5-yl]- 513 Meth 2-{4-[N-(2-methoxyethyl)-N-t- 98 butylsulphamoyl]anilino}pyrimidine

Method 112 N-(2-Methoxyethyl)-N-(2-trimethylsilylethoxymethyl)-4-iodobenzenesulphonamide

Sodium hydride (2.2 g, 55 mmol), was added to a solution of N-(2-methoxyethyl)-4-iodobenzenesulphonamide (Method 4; 15.8 g, 46.3 mmol), in DMF (250 ml), under nitrogen at 0° C. and the mixture stirred for 1 hour. 2-Trimethylsilylethoxymethyl chloride (10 g, 60 mmol), was added and the mixture stirred overnight at ambient temperature. The volatiles were removed by evaporation and the residue dissolved in ether, washed with water and then brine, dried (Na₂SO₄), and the solvent evaporated to give the title compound (22.6 g, 74%). NMR: 0.2 (s, 9H, 0.89 (t, 2H), 3.30 (s, 3H), 3.40-3.36 (m, 2H), 3.59-3.43 (m, 2H), 4.82 (s, 2H), 7.60 (d, 2H), 7.84 (d, 2H).

Method 113 N-(2-Methoxyethyl)-N-(t-butyl)-4-iodobenzenesulphonamide

Sodium hydride (71 mg, 1.77 mg), was added to a solution of N-t-butyl-4-iodobenzenesulphonamide (Method 5; 500 mg, 1.47 mmol), in anhydrous DMF (15 ml), under nitrogen at 0° C. The resulting suspension was stirred at 0° C. for 30 minutes. A solution of 1-bromo-2-methoxyethane (167 μl, 1.77 mmol), and sodium iodide (265 mg, 1.77 mmol), in DMF (1 ml), (pre-stirred at ambient temperature for 1 hr), was then added dropwise to the mixture while the, reaction temperature was maintained at 0° C. and the mixture stirred for 10 minutes. The mixture was allowed to warm to ambient temperature, and then heated at 60° C. for 20 hours. A further solution of 1-bromo-2-methoxyethane (167 μl, 1.77 mmol), and sodium iodide (265 mg, 1.77 mmol), in DMF (15 ml), (pre-stirred at ambient temperature for 1 hr), was then added dropwise to the mixture at ambient temperature and the reaction mixture was heated at 60° C. for 20 hours. The mixture was cooled and solvent removed by evaporation. The residue was dissolved in ether (25 ml), washed with 10% aqueous sodium hydroxide solution (20 ml), water (3×25 ml), and dried. The volatiles were removed by evaporation and the residue purified by flash chromatography on silica gel eluting with DCM to yield the title product as a clear oil that crystallised on standing (147 mg, 25%), NMR: 1.23 (s, 9H), 3.24 (s, 3H), 3.48 (s, 4H), 7.57 (d, 2H), 7.94 (d, 2H).

Method 114 4-[2-(3,3-Dimethylbut-1-en-1-yl)-1-(propyl)imidazol-5-yl]-2-anilinopyrimidine

Triethylamine (0.74 ml, 5.05 mmol), followed by methane sulphonyl chloride (0.103 ml, 1.33 mmol) was added to a stirred solution of 4-[2-(3,3-dimethyl-2-hydroxybut-1-yl)-1-(propyl)imidazol-5-yl]-2-anilinopyrimidine (Method 101; 480 mg, 1.26 mmol) in DCM (40 ml) at ambient temperature and the mixture stirred for 24 hours. The volatiles were removed by evaporation and toluene (10 ml), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 ml, 2.54 mmol) was added to the residue. The mixture was heated at reflux for 5 hours, allowed to cool, washed with water and extracted with EtOAc. The extracts were combined, dried and the solvent removed by evaporation to give the title compound (240 mg, 53%). NMR: 0.64 (t, 3H), 1.15 (s, 9H), 1.53 (q, 2H), 4.64 (t, 2H), 6.38 (d, 1H), 6.80 (d, 1H), 6.99 (t, 1H), 7.10 (d, 1H), 7.28 (t, 2H), 7.62 (d, 3H), 7.75 (s, 1H), 8.38 (d, 1H), 9.38 (s, 1H); m/z 362.

Method 115 4-[2-(3,3-Dimethylbutyl)-1-(propyl)imidazol-5-yl]-2-anilinopyrimidine

A mixture of 10% palladium on charcoal catalyst (100 mg), 4-[2-(3,3-dimethylbut-1-en-1-yl)-1-(propyl)imidazol-5-yl]-2-anilinopyrimidine (Method 114; 230 mg, 0.64 mmol) in ethanol (50 ml) was stirred under an atmosphere of hydrogen for 72 hours. The catalyst was removed by filtration through diatomaceous earth, and the filter pad washed with warm MeOH. The solvent removed by evaporation to give the title compound (200 mg, 86%). M/z 364.

Method 116 4-[2-(Chloromethyl)-1-(propyl)imidazol-5-yl]-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine

Chlorosulphonic acid (2.29 g, 20 mmol) was added dropwise to a stirred solution of 2-anilino-4-(1-propyl-2-methoxymethylimidazol-5-yl)pyrimidine (Method 75; 1.29 g, 4.0 mmol) in thionyl chloride (30 ml), cooled to 0-4° C. The solution was allowed to warm to ambient temperature and was then heated under reflux for 18 hour. The mixture was cooled and an oil separated out. The excess thionyl chloride was decanted from this oil, and the residue was washed with thionyl chloride (10 ml) and any volatiles removed by evaporation. The residue was dissolved in MeOH (15 ml), cooled to 0-4° C. and a solution of 2-ethoxyethylamine (3.56 g, 40 mmol) in cold MeOH (15 ml) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for one hour. The mixture was allowed to stand and cooled to 0-4° C. The resulting crystalline product was collected by filtration, washed with MeOH and dried to give the title compound (587 mg, 31%). NMR: 0.70 (t, 3H), 1.05 (t, 3H), 1.55 (m, 2H), 2.86 (m, 2H), 3.33 (m, 4H), 4.60 (t, 2H), 4.95 (s, 2H), 7.25 (d, 1H), 7.46 (t, 1H), 7.71 (d, 2H), 7.75 (s, 1H), 7.86 (d, 2H), 8.50 (d, 1H), 9.90 (s, 1H); m/z 479.

Method 117 4-{2-[2-(4-Chlorophenyl)ethyl]-1-(methyl)imidazol-5-yl}-2-{4-[N-(2-methoxyethyl) sulphamoyl]anilino}pyrimidine

4-{2-[2-(4-Chlorophenyl)ethyl]-1-(methyl)imidazol-5-yl}-2-anilinopyrimidine (Method 102) was treated with 2-methoxyethylamine by the conditions described in Method 116. The crude product was purified by chromatography on silica gel eluting with DCM/MeOH (98:2) to give the title compound (164 mg, 48%) as glassy solid. NMR: 2.88 (q, 2H), 3.02 (s, 4H), 3.15 (s, 3H), 3.26 (m, 2H), 3.92 (s, 3H), 7.21 (d, 1), 7.32 (d, 4H), 7.44 (s, 1H), 7.66 (s, 1H), 7.68 (d, 2H), 7.90 (d, 2H), 8.44 (d, 1H), 9.92 (s, 1H); m/z 528.

Method 118 2-Anilino-4-(2-formyl-1-propylimidazol-5-yl)pyrimidine

2-Anilino-4-(1-propylimidazol-5-yl)pyrimidine (Method 84) was treated as described in Method 105. The crude product was purified by chromatography on silica gel eluting with EA/IsoHex) (80:20) to give the title compound (1.051 g, 48%) as a yellow solid. NMR: 0.63 (t, 3H), 1.59 (m, 2H), 4.94 (t, 2H), 7.01 (t, 1H), 7.30 (m, 3H), 7.63 (d, 2H), 8.0 (s, 1H), 8.55 (d, 1H), 9.60 (s, 1H), 9.80 (s, 1H).

Method 119 2-Anilino-4-(2-dimethylaminomethyl-1-propylimidazol-5-yl)pyrimidine

A mixture of 2-anilino 4-(2-formyl-1-propylimidazol-5-yl)pyrimidine (Method 118; 200 mg, 0.65 mmol) and dimethylamine (391 μl of 2M solution in THF, 0.78 mmol) in MeOH (6 ml) stirred for 3 hours at ambient temperature. Acetic acid (41 mg, 0.716 mmol) and sodium cyanoborohydride (45 mg, 0.716 mmol) were added and the mixture stirred for a further 18 hours. The volatiles were removed by evaporation and residue dissolved in EtOAc (7 ml). This solution was washed with saturated aqueous sodium hydrogen carbonate solution, water, and brine, then dried and the solvent removed by evaporation to give the title compound (210 mg, 96%) as a yellow foam. NMR: 0.62 (t, 6H), 1.50 (m, 2H), 2.23 (s, 6H), 3.60 (s, 2H), 4.56 (m, 2H), 6.98 (t, 1H), 7.10 (d, 1H), 7.28 (t, 2H), 7.62 (m, 3H), 8.39 (d, 1H), 9.39 (s, 1H); m/z 337.

Method 120 2-Anilino 4-(2-ethylamniomethyl-1-propylimidazol-5-yl)pyrimidine

2-Anilino 4-(2-formyl-1-propylimidazol-5-yl)pyrimidine (Method 118) was treated with ethylamine (2M solution in MeOH) by the procedure of Method 119 to give the title compound (185 mg, 93%) as a yellow foam. M/z 337.

Example 87

The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof (hereafter compound X), for therapeutic or prophylactic use in humans:— (a): Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate 3.0

(b): Tablet II mg/tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0

(c): Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0

(d): Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium stearate 1.5

(e): Injection I (50 mg/ml) Compound X 5.0% w/v 1M Sodium hydroxide solution 15.0% v/v 0.1M Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100%

(f): Injection II 10 mg/ml Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v 0.1M Sodium hydroxide solution 15.0% v/v Water for injection to 100%

(g): Injection III (1 mg/ml, buffered to pH6) Compound X 0.1% w/v Sodium phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 400 3.5% w/v Water for injection to 100%

Note

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. 

1. A compound of formula (I):

wherein: R¹ is halo, cyano, C₁₋₃alkyl or C₁₋₃alkoxy; p is 0-2; wherein the values of R¹ may be the same or different; R² is hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl, a heterocyclyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more hydroxy, methyl, ethyl, methoxy, ethoxy, propoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy or cyclopropylmethoxy; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by one or more methyl, ethyl, acetyl, 2,2,2-trifluoroethyl or methoxyethyl; R³ is hydrogen, halo or cyano; R⁴ is C₁₋₆alkyl or C₁₋₆alkoxyC₁₋₆alkyl; R⁵ is substituted methyl, optionally substituted C₂₋₆alkyl, C₃₋₆cycloalkyl or optionally substituted C₂₋₆alkenyl; wherein said substituents are selected from one or more hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, phenyl, methylamino, ethylamino, dimethylamino, diethylamino, methylthio, ethylthio, propylthio, isopropylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl, isopropylsulphinyl, methylsulphonyl, ethylsulphonyl, propylsulphonyl, isopropylsulphonyl or cyclopropylmethoxy; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; provided that the compound is not 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine; or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4[N-(2-methoxyethyl) sulphamoyl]anilino}pyrimidine.
 2. A compound of formula (I) according to claim 1 wherein p is 0; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
 3. A compound of formula (I) according to either claim 1 or claim 2 wherein R² is hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkylC₁₋₃alkyl or heterocyclylC₁₋₃alkyl; wherein R² may be optionally substituted on carbon by one or more hydroxy, methoxy, ethoxy or trifluoromethyl; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
 4. A compound of formula (I) according to any one of claims 1-3 wherein R³ is hydrogen; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
 5. A compound of formula (I) according to any one of claims 14 wherein R⁴ is C₁₋₄alkyl or C₁₋₄alkoxyC₁₋₄alkyl; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
 6. A compound of formula (I) according to any one of claims 1-5 wherein R⁵ is substituted methyl, optionally substituted C₂alkyl, C₃₋₆cycloalkyl or optionally substituted C₂₋₆alkenyl; wherein said substituents are selected from one or more hydroxy, methoxy, ethoxy, isopropoxy, phenyl, ethylamino, dimethylamino, methylthio, ethylthio, isopropylthio, ethylsulphinyl or ethylsulphonyl; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
 7. A compound of formula (I) as depicted in claim 1 wherein: p is 0; R² is hydrogen, 2-ethoxyethyl, 2-methoxyethyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 3-methoxypropyl, t-butyl, allyl, cyclopropyl, cyclobutyl, cyclopropylmethyl or tetrahydrofur-2-ylmethyl; R³ is hydrogen; R⁴ is methyl, ethyl, propyl, isopropyl or 1-methoxyprop-2-yl; or R⁵ is methoxymethyl, 2-methoxyethyl, 2-hydroxy-2-methylpropyl, propyl, isopropyl, ethyl, butyl, isobutyl, cyclopropyl, 2-methyl-1-propenyl, 3-butenyl, 1-propenyl, 3,3-dimethylbutyl, phenethyl, dimethylaminomethyl, ethylaminomethyl, ethoxymethyl, methylthiomethyl, isopropylthiomethyl, ethylthiomethyl, ethylsulphinlmethyl, ethylsulphonylmethyl or isopropoxymethyl; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; provided that the compound is not 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-isopropyl-imidazol-5-yl)-2-{4-[N-(tetrahydrofur-2-ylmethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-{4-[N-(cyclopropylmethyl)sulphamoyl]anilino)pyrimidine; 4-(1-methyl-2-ethyl-imidazol-5-yl)-2-[4-(N-cyclopropylsulphamoyl)anilino]pyrimidine; 4-(1-methyl-2-ethylimidazol-5-yl)-2-[4-(N-cyclobutyl-sulphamoyl)anilino]pyrimidine; or 4-(1-methyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl) sulphamoyl]anilino}pyrimidine.
 8. A compound of formula (I) as depicted in claim 1 selected from: 4-(1,2-diethylimidazol-5-yl)-2-(4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-isopropyl-2-methoxymethylimidazol-5-yl)-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1,2-diethylimidazol-5-yl)-2-{4-[N-(cyclopropyl)sulphamoyl]anilino}pyrimidine; 4-(1,2-diethylimidazol-5-yl)-2-{4-[N-(allyl)sulphamoyl]anilino}pyrimidine; 4-(1-isopropyl-2-cyclopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-methyl-2-propylimidazol-5-yl)-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-ethyl-2-propylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-isopropyl-2-propylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; 4-(1-isopropyl-2-ethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine; and 4-(1-isopropyl-2-ethylimidazol-5-yl)-2-{4-[N-(2-ethoxyethyl)sulphamoyl]anilino}pyrimidine; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof;
 9. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof which process (wherein R¹, R², R³, R⁴, R⁵ and p are, unless otherwise specified, as defined in claim 1) comprises of: Process a) reaction of a pyrimidine of formula (II):

wherein L is a displaceable group; with an aniline of formula (III):

Process b) reacting a compound of formula (I:

with a compound of formula (V):

wherein T is O or S; R^(x) may be the same or different and is C₁₋₆alkyl; Process c) reacting a pyrimidine of formula (VI):

wherein X is a displaceable group; with an amine of formula (VII): R²—NH₂  (VII) or Process d) reacting a pyrimidine of formula (VIII)

with a compound of formula (IX):

where Y is a displaceable group; and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.
 10. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-8, in association with a pharmaceutically-acceptable diluent or carrier.
 11. A compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-8, for use in a method of treatment of the human or animal body by therapy.
 12. A compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-8, for use as a medicament.
 13. The use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-8, in the manufacture of a medicament for use in the production of a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal such as man.
 14. The use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-8, in the manufacture of a medicament for use in the treatment of cancers (solid tumours and leukaemias), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.
 15. The use of a compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-8, in the manufacture of a medicament for use in the treatment of cancer.
 16. The use according to claim 15 wherein the cancer is selected from leukaemia, breast cancer, lung cancer, colorectal cancer, stomach cancer, prostate cancer, bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, kidney cancer, skin cancer and cancer of the vulva.
 17. A compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-8, for use in the production of a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal such as man.
 18. A compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-8, for use in the treatment of cancers (solid tumours and leukaemias), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.
 19. A compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-8, for use in the treatment of cancer.
 20. A compound of the formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1-8, for use in the treatment of leukaemia, breast cancer, lung cancer, colorectal cancer, stomach cancer, prostate cancer, bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, kidney cancer, skin cancer and cancer of the vulva. 